USPTO Patents Application 09993647

ENTED

LAW OFFICES
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.

Arlington Co urinous* Plaza 1
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2200 Clarendon Boulevard
Arlington, Virginia 22201

ATTY:

PATENTED

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(o-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors

10 Cross-Reference to Related Applications

This is a continuation-in-part of Serial No. 09/257,266 filed February 25, 1999 and a
continuation-in-part of Serial No. 60/1 15,877. filed January 13, 1999.

Field of the Invention

15 This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and
pharmaceutical compositions for use in such therapy.

Background of the Invention

The p21 ras oncogene is a major contributor to the development and progression of human
20 solid cancers and is mutated in 30% of all human cancers (Bolton et al. Ann. Rep. Med.
Chem, 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its normal, unmutated form,
the ras protein is a key element of the signal transduction cascade directed by growth factor
receptors in almost all tissues (Avruch et al. Trends^ Biochem. Sci. 1994, 79, 279-83).
Biochemically, ras is a guanine nucleotide binding protein, and cycling between a GTP-
25 bound activated and a GDP-bound resting form is strictly controlled by ras' endogenous
GTPase activity and other regulatory proteins. In the ras mutants in cancer cells, the
endogenous GTPase activity is alleviated and, therefore, the protein delivers constitutive
growth signals to downstream effectors such as the enzyme raf kinase. This leads to the
cancerous growth of the cells which carry these mutants (Magnuson et al. Semin. Cancer
30 Biol. 1994, 5, 247-53). It has been shown that inhibiting the effect of active ras by inhibiting
the raf kinase signaling pathway by administration of deactivating antibodies to raf kinase or
by co-expression of dominant negative raf kinase or dominant negative MEK. the substrate of

1

raf kinase, leads to the reversion of transformed cells to the normal growth phenotype (see:
Daum et al. Trends Biochem. Sci. 1994, 79, 474-80; Fridman et al. J. Biol. Chem. 1994, 269,
30105-8. Kolch et al. {Nature 1991, 349, 426-28) have further indicated that inhibition of raf
expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes.
5 Similarly, inhibition of raf kinase (by antisense oiigodeoxynucleotides) has been correlated in
vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et
al., Nat. Med. 1996, 2, 668-75).

Summary of the Invention

10 The present invention provides compounds which are inhibitors of the enzyme raf kinase.
Since the enzyme is a downstream effector of p21 ras , the inhibitors are useful in
pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase
pathway is indicated, e.g., in the treatment of tumors and/or cancerous cell growth mediated
by raf kinase. In particular, the compounds are useful in the treatment of human or animal

15 solid cancers, e.g., murine cancer, since the progression of these cancers is dependent upon
the ras protein signal transduction cascade and therefore susceptible to treatment by
interruption of the cascade, i.e., by inhibiting raf kinase. Accordingly, the compounds of the
invention are useful in treating cancers, including solid cancers, such as, for example,
carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or colon), myeloid disorders (e.g.,

20 myeloid leukemia) or adenomas (e.g., villous colon adenoma).

The present invention therefore provides compounds generally described as aryl ureas,
including both aryl and heteroaryl analogues, which inhibit the raf kinase pathway. The
invention also provides a method for treating a raf mediated disease state in humans or
25 mammals. Thus, the invention is directed to compounds which inhibit the enzyme raf kinase
and also compounds, compositions and methods for the treatment of cancerous cell growth
mediated by raf kinase wherein a compound of Formula I is administered or pharmaceutical^
acceptable salt thereof.

A - D - B (I)

30 In formula I, D is -NH-C(0)-NH-,

2

A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L l ) q ,
where L is a 5 or 6 membered cyclic structure bound directly to D, L 1 comprises a
substituted cyclic moiety having at least 5 members, M is a bridging group having at least
one atom, q is an integer of from 1-3; and each cyclic structure of L and L 1 contains 0-4
5 members of the group consisting of nitrogen, oxygen and sulfur, and

B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to
30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing
0-4 members of the group consisting of nitrogen, oxygen and sulfur,

wherein L 1 is substituted by at least one substituent selected from the group consisting
10 of -S0 2 Rx, -C(0)R x and -C(NR y ) R z ,

R y is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally
containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per
halo,

R z is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally
15 containing heteroatoms selected from N, S and O and optionally substituted by halogen,
hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain
heteroatoms selected from N, S and O and are optionally substituted by halogen;

R x is R z or NR a Rb where Ra and R b are

a) independently hydrogen,

20 a carbon based moiety of up to 30 carbon atoms optionally containing

heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and
carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms
selected from N, S and O and are optionally substituted by halogen, or

-OSi(Rf). 3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon
25 atoms optionally containing heteroatoms selected from N, S and O and optionally substituted
by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which
optionally contain heteroatoms selected from N, S and O and are optionally substituted by

halogen; or

3

b) R a and R b together form a 5-7 member heterocyclic structure of 1-3
heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of
1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based
substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N,

5 S and O and are optionally substituted by halogen; or

c) one of R a or R b is -C(O)-, a C1-C5 divalent alkylene group or a substituted d-
C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5
members, wherein the substituents of the substituted C1-C5 divalent alkylene group are
selected from the group consisting of halogen, hydroxy, and carbon based substituents of up

10 to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are
optionally substituted by halogen;

where B is substituted, L is substituted or L l is additionally substituted, the
substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where
n is 0-3;

15 wherein each W is independently selected from the group consisting of -CN, -C0 2 R 7 ,

-C(0)NR 7 R 7 , -C(0)-R 7 , -N0 2 , -OR 7 , -SR 7 , -NR 7 R 7 , -NR 7 C(0)OR 7 , -NR 7 C(0)R 7 , -Q-Ar, and
carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected
from N, S and O and optionally substituted by one or more substituents independently
selected from the group consisting of -CN, -C0 2 R 7 , -C(0)R 7 , -C(0)NR 7 R 7 , -OR 7 , -SR 7 , -

20 NR 7 R 7 , -N0 2 , -NR 7 C(0)R 7 , -NR 7 C(0)OR 7 and halogen up to per-halo; with each R 7
independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally
containing heteroatoms selected from N, S and O and optionally substituted by halogen,

wherein Q is -O-, -S-, -N(R 7 )-, -(CH 2 ) m -, -C(O)-, -CH(OH)-, -(CH 2 ) m O-, -(CH 2 ) m S-,
-(CH 2 ) m N(R 7 )-, -0(CH 2 ) m - CHX a -, -CXV, -S-(CH 2 ) m - and -N(R 7 )(CH 2 ) m -, where m= 1-3,
25 and X a is halogen; and

Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the
group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen,
up to per-halo, and optionally substituted by Z n i, wherein nl is 0 to 3 and each Z is
independently selected from the group consisting of -CN, -C0 2 R , -C(0)R\ -C(0)NR R . -
30 NO : , -OR 7 , - SR 7 -NR 7 R 7 , -NR 7 C(0)OR 7 , -NR 7 C(0)R 7 , and a carbon based moiety of up to

4

24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally
substituted by one or more substituents selected from the group consisting of -CN, -CO2R , -
COR 7 , -C(0)NR 7 R 7 , -OR 7 , -SR 7 , -N0 2 , -NR 7 R 7 , -NR 7 C(0)R 7 , and -NR 7 C(0)OR 7 , with R 7 as
defined above.

5

In formula I, suitable hetaryl groups include, but are not limited to, 5-12 carbon-atom
aromatic rings or ring systems containing 1-3 rings, at least one of which is aromatic, in
which one or more, e.g., 1-4 carbon atoms in one or more of the rings can be replaced by
oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms. For example, B can be

10 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl,
1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-,
4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-l-, -4- or -5-
yl, 1,2,4-triazol-l-, -3- or -5-yl, 1- or 5-tetrazolyl, l,2,3-oxadiazol-4- or -5-yl, 1,2,4-
oxadiazol-3- or -5-yl, l,3,4-thiadiazoI-2- or -5-yl, l,2,4-oxadiazol-3- or -5-yl, 1,3,4-

15 thiadiazol-2- or -5-yl, l,3,4-thiadiazol-3- or -5-yl, l,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5-
or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-,
6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-,
4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl,
3- } 4- ? 5- 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-

20 benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benz-l,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl,
3-, 4-, 5-, 6-, 7-, 8- isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyI, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-
or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally optionally substituted
phenyl, 2- or 3-thienyl, 1,3, 4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl,
etc. For example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, 1-

25 methyl-3-pyrryl, l-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl-l,2,4-thiadiazol-2-

yi-

Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy, etc. throughout
include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched isomers
such as isopropyl, isobutyl, sec-butyl, rerr-butyl, etc.
30 Suitable aryl groups which do not contain heteroatoms include, for example, phenyl

and I - and 2-naphthyl.

5

The term "cycloalkyl", as used herein, refers to cyclic structures with or without alkyl
substituents such that, for example, "C4 cycloalkyl" includes methyl substituted cyclopropyl
groups as well as cyclobutyl groups. The term "cycloalkyl", as used herein also includes
saturated heterocyclic groups.
5 Suitable halogen groups include F, CI, Br, and/or I, from one to per-substitution (i.e.

all H atoms on a group replaced by a halogen atom) being possible where an alkyl group is
substituted by halogen, mixed substitution of halogen atom types also being possible on a
given moiety.

The invention also relates to compounds per se, of formula I.

10

The present invention is also directed to pharmaceutically acceptable salts of formula I.
Suitable pharmaceutically acceptable salts are well known to those skilled in the art and
include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic
acid, sulfuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid,

15 benzenesulfonic acid, /?-toluenesulfonic acid, 1 -naphthalenesulfonic acid, 2-
naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid,
lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,
phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include
acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li + Na + or K + ),

20 alkaline earth cations (e.g., Mg +2 , Ca +2 or Ba +2 ), the ammonium cation, as well as acid salts
of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary
ammonium cations, such as those arising from protonation or peralkylation of triethylamine,
A^iV-diethylamine, Af AMicyclohexylamine, lysine, pyridine, AfA^dimethylaminopyridine
(DMAP), l,4-diazabiclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN)

25 and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

A number of the compounds of Formula I possess asymmetric carbons and can therefor exist
in racemic and optically active forms. Methods of separation of enantiomeric and
diastereomeric mixtures are well known to one skilled in the art. The present invention

30 encompasses any isolated racemic or optically active form of compounds described in
Formula I which possess raf inhibitory activity.

6

General Preparative Methods

The compounds of Formula I may be prepared by the use of known chemical reactions and
procedures, some from starting materials which are commercially available. Nevertheless,
general preparative methods are provided below to aid one skilled in the art in synthesizing
these compounds, with more detailed examples being provided in the Experimental section
which follows.

Substituted anilines may be generated using standard methods (March. Advanced Organic
Chemistry, 3 rd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic
Transformations', VCH Publishers: New York (1989)). As shown in Scheme I, aryl amines
are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or
Pt, and H2 or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride
(Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls may
also be directly reduced using a strong hydride source, such as LiALHU (Seyden-Penne.
Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New
York (1991)), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic media. Many
methods exist for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3 rd Ed.;
John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH
Publishers: New York (1989)).

H 2 / catalyst

ArN0 2

^ ArNH 2

(eg. Fe, Sn, Ca)

Scheme I

Reduction of Nitroaryls to Aryl Amines

Nitroaryls are commonly formed by electrophilic aromatic nitration using HNOi, or an
alternative source. Nitroaryls may be further elaborated prior to reduction. Thus,

nitroaryls substituted with

HNQ 3

Ar-H

ArNQ 2

potential leaving groups (e.g. F, CI, Br, etc.) may undergo substitution reactions on treatment
with nucleophiles, such as thiolate (exemplified in Scheme II) or phenoxide. Nitroaryls may
also undergo Ullman-type coupling reactions (Scheme II).

Scheme II Selected Nucleophilic Aromatic Substitution using Nitroaryls

Nitroaryls may also undergo transition metal mediated cross coupling reactions. For
example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, undergo
palladium mediated cross coupling reactions with aryl nucleophiles, such as arylboronic acids
10 (Suzuki reactions, exemplified below), aryltins (Stille reactions) or arylzincs (Negishi
reaction) to afford the biaryl (5).

Either nitroaryls or anilines may be converted into the corresponding arenesulfonyl chloride
(7)' on treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride
15 source, such as KF then affords sulfonyl fluoride (8). Reaction of sulfonyl fluoride 8 with
trimethylsilyl trifluoro me thane in the presence of a fluoride source, such as
tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to the corresponding
trifluoromethylsulfone (9). Alternatively, sulfonyl chloride 7 may be reduced to the
arenethiol (10), for example with zinc amalgum. Reaction of thiol 10 with CHC1F : in the

5

3

4

5

8

presence of base gives the difluoromethyl mercaptam (11), which may be oxidized to the
sulfone (12) with any of a variety of oxidants, including Cr03-acetic anhydride (Sedova et al.
Zh. Org. Khim, 1970, 6, (568).

[O]

T

S0 2 CHF 2

5 Scheme III Selected Methods of Fluorinated Aryl Sulfone Synthesis

As shown in Scheme IV, non-symmetrical urea formation may involve reaction of an aryl
isocyanate (14) with an aryl amine (13). The heteroaryl isocyanate may be synthesized from
a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as
tnchloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or
10 M iV'-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic
carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius-type
rearrangement. Thus, reaction of acid derivative 16 with an azide source, followed by
rearrangement affords the isocyanate. The corresponding carboxylic acid (17) may also be

9

subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPP A) or a
similar reagent.

Ar 1 — NH 2 13

COCI 2

H 2 N— Ar 2

O

Ar'-NCO

14

15

DPPA

O

O

Ar

,iA x

Ar

■A.

OH

16

17

Scheme IV Selected Methods of Non-Symmetrical Urea Formation

Finally, ureas may be further manipulated using methods familiar to those skilled in the art.

The invention also includes pharmaceutical compositions including a compound of Formula
I, and a physiologically acceptable carrier.

The compounds may be administered orally, topically, parenterally, by inhalation or spray or
rectally in dosage unit formulations. The term 'administration by injection' includes
intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion
techniques. One or more compounds may be present in association with one or more non-
toxic pharmaceutically acceptable carriers and if desired other active ingredients.

Compositions intended for oral use may be prepared according to any suitable method known
to the art for the manufacture of pharmaceutical compositions. Such compositions may
contain one or more agents selected from the group consisting of diluents, sweetening agents,
flavoring agents, coloring agents and preserving agents in order to provide palatable
preparations. Tablets contain the active ingredient in admixture with non-toxic
pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
These excipients may be, for example, inert diluents, such as calcium carbonate, sodium

10

carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating
agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium
stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known
techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby
5 provide a sustained action over a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate may be employed. These compounds may also
be prepared in solid, rapidly released form.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active
io ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with
water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for
15 the manufacture of aqueous suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium
alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents
may be a naturally occurring phosphatide, for example, lecithin, or condensation products or
an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation
20 products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene
oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty
acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of
ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for
example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one
25 or more preservatives, for example ethyl, or n-propyl /?-hydroxybenzoate, one or more
coloring agents, one or more flavoring agents, and one or more sweetening agents, such as
sucrose or saccharin.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the
30 addition of water provide the active ingredient in admixture with a dispersing or wetting
agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents

11

and suspending agents are exemplified by those already mentioned above. Additional
excipients, for example, sweetening, flavoring and coloring agents, may also be present.

The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily
5 suspensions which may be formulated by suspending the active ingredients in a vegetable oil,
for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard
paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring
agents may be added to provide palatable oral preparations. These compositions may be
10 preserved by the addition of an anti-oxidant such as ascorbic acid.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water
emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a
mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents
15 may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-
occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation
products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and flavoring agents.

20

Syrups and elixirs may be formulated with sweetening agents, for example glycerol,
propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a
preservative and flavoring and coloring agents.

25 The compounds may also be administered in the form of suppositories for rectal
administration of the drug. These compositions can be prepared by mixing the drug with a
suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal
temperature and will therefore melt in the rectum to release the drug. Such materials include
cocoa butter and polyethylene glycols.

30

For all regimens of use disclosed herein for compounds of Formula I, the daily oral dosage
regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily dosage

12

for administration by injection, including intravenous, intramuscular, subcutaneous and
parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200
mg/Kg of total body weight. The daily rectal dosage regime will preferably be from 0.01 to
200 mg/Kg of total body weight. The daily topical dosage regime will preferably be from 0.1
5 to 200 mg administered between one to four times daily. The daily inhalation dosage regime
will preferably be from 0.01 to 10 mg/Kg of total body weight.

It will be appreciated by those skilled in the art that the particular method of administration
will depend on a variety of factors, all of which are considered routinely when administering

10 therapeutics. It will also be appreciated by one skilled in the art that the specific dose level
for a given patient depends on a variety of factors, including specific activity of the
compound administered, age, body weight, health, sex, diet, time and route of administration,
rate of excretion, etc. It will be further appreciated by one skilled in the art that the optimal
course of treatment, ie., the mode of treatment and the daily number of doses of a compound

15 of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of
days, can be ascertained by those skilled in the art using conventional treatment tests.

It will be understood, however, that the specific dose level for any particular patient will
depend upon a variety of factors, including the activity of the specific compound employed,
20 the age, body weight, general health, sex, diet, time of administration, route of administration,
and rate of excretion, drug combination and the severity of the condition undergoing therapy.

The entire enclosure of all applications, patents and publications cited above and below are
hereby incorporated by reference, including provisional application Serial No. 60/115,877,
25 filed January 13, 1999 and non-provisional application Serial No. 09/257,266 filed February
25,1999.

The compounds can be produced from known compounds (or from starting materials which,
in turn, can be produced from known compounds), e.g., through the general preparative
30 methods shown below. The activity of a given compound to inhibit raf kinase can be
routinely assayed, e.g., according to procedures disclosed below. The following examples

T

are for illustrative purposes only and are not intended, nor should they be construed to limit
the invention in any way.

EXAMPLES

5 All reactions were performed in flame-dried or oven-dried glassware under a positive
pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise
indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and
introduced into reaction vessels through rubber septa. Unless otherwise stated, the term
'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at

10 approximately 15 mmHg. Unless otherwise stated, the term 'under high vacuum' refers to a
vacuum of 0.4 - 1.0 mmHg.

All temperatures are reported uncorrected in degrees Celsius (°C). Unless otherwise
indicated, all parts and percentages are by weight.

15

Commercial grade reagents and solvents were used without further purification.
cyclohexyl-A/' , -(methylpolystyrene)carbodiimide was purchased from Calbiochem-
Novabiochem Corp. 3-terf-Butylaniline, 5-/erf-butyl-2-methoxyaniline, 4-bromo-3-
(trifluoromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniline 2-methoxy-5-

20 (trifluoromethyl)aniline, 4-rerf-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-
isocyanatobenzoate, iV-acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and 4-chloro-3-
(trifluoromethyl)phenyl isocyanate were purchased and used without further purification.
Syntheses of 3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP
542,609; IBID Bioorg. Med. Chem.. 3, 1995, 129), 4-(3-carbamoylphenoxy)-l -nitrobenzene

25 (K. Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3-tert-
butylphenyl isocyanate (O. Rohr et al. DE 2,436,108) and 2-methoxy-5-
(trifluoromethyl)phenyl isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo Kagaku
Zasshi 70, 1967, 491) have previously been described.

30 Thin-layer chromatography (TLC) was performed using Whatman" pre-coated glass-backed
silica gel 60A F-254 250 \xm plates. Visualization of plates was effected by one or more of
the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c)

14

T

immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by
heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or
(e) immersion of the plate in an acidic ethanol solution of 2 } 4-dinitrophenylhydrazine
followed by heating. Column chromatography (flash chromatography) was performed using
230-400 mesh EM Science silica gel.

Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a
Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform
infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer.
Proton ( l H) nuclear magnetic resonance (NMR) spectra were measured with a General
Electric GN-Omega 300 (300 MHz) spectrometer with either Me 4 Si (5 0.00) or residual
protonated solvent (CHC1 3 5 7.26; MeOH 5 3.30; DMSO 5 2.49) as standard. Carbon ( l3 C)
NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer
with solvent (CDC1 3 5 77.0; MeOD-d 3 ; 5 49.0; DMSO-da 5 39.5) as standard. Low resolution
mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron
impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact
mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer
equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction.
The ion source was maintained at 250 °C. Electron impact ionization was performed with
electron energy of 70 eV and a trap current of 300 ^A. Liquid-cesium secondary ion mass
spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a
Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained
using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas
(lxlO" 4 torr to 2.5xl0" 4 torr). The direct insertion desorption chemical ionization (DCI) probe
(Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all
traces of the sample disappeared ( -1-2 min). Spectra were scanned from 50-800 amu at 2
sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a
Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength
detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray
ionization. Spectra were scanned from 120-800 amu using a variable ion time according to
the number of ions in the source. Gas chromatography - ion selective mass spectra (GC-MS)

15

were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1
methyl silicone column (0.33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard 5971
Mass Selective Detector (ionization energy 70 eV). Elemental analyses are conducted by
Robertson Microlit Labs, Madison NJ.

5

All compounds displayed NMR spectra, LRMS and either elemental analysis or HRMS
consistent with assigned structures.

List of Abbreviations and Acronyms:

10 AcOH acetic acid

anh anhydrous

atm atmosphere(s)

BOC terr-butoxycarbonyl

CDI l,r-carbonyl diimidazole

15 cone concentrated

d day(s)

dec decomposition

DM AC Af,Af-dimethylacetamide

DMPU l ) 3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone

20 DMF Af A^dimethylformamide

DMSO dimethylsulfoxide

DPPA diphenylphosphoryl azide

EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide

EtOAc ethyl acetate

25 EtOH ethanol(100%)

Et 2 0 diethyl ether

Et3N triethylamine

h hour(s)
HOBT 1 -hydroxybenzotriazole

30 w-CPBA 3-chloroperoxybenzoic acid

MeOH methanol

pet. ether petroleum ether (boiling range 30-60 °C)

16

temp.

Tf

THF

TFA

temperature
tetrahydrofuran
tnfluoroAcOH
trifluoromethanesulfonyl

5

Al.

A.

General Methods for Synthesis of Substituted Anilines
General Method for Aryl Amine Formation via Ether Formation
Followed by Ester Saponification, Curtius Rearrangement, and
Carbamate Deprotection. Synthesis of 2-Amino-3-methoxynaphthalene.

CQ 2 Me

10

OMe

Step 1.

Methyl 3-methoxy-2-naphthoate

A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K 2 C0 3 (7.96 g, 57.6
mmol) in DMF (200 mL) was stirred at room temp, for 15 min., then treated with
iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room temp.
15 overnight, then was treated with water (200 mL). The resulting mixture was extracted with
EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated NaCl
solution (100 mL), dried (MgS0 4 ), concentrated under reduced pressure (approximately 0.4
mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil (10.30 g): ! H-

NMR (DMSO-d 6 ) 5 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J=8.09 Hz, 1H), 7.44 (s, 1H), 7.53
20 (app t, y=8.09 Hz, 1H), 7.84 (d, J=8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).

A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in
MeOH (100 mL) at room temp, was treated with a 1 N NaOH solution (33.4 mL, 33.4 mmol).
25 The mixture was heated at the reflux temp, for 3 h, cooled to room temp., and made acidic
with a 10% citric acid solution. The resulting solution was extracted with EtOAc (2 x 100

OMe

Step 2.

3-Methoxy-2-naphthoic acid

17

mL). The combined organic layers were washed with a saturated NaCl solution, dried
(MgSOa) and concentrated under reduced pressure. The residue was triturated with hexane
then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid
(5.40 g, 92%): ] H-NMR (DMSO-d 6 ) 5 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H),
5 7.83 (d, J=8.09 Hz, 1H), 7.91 (d, 7-8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (br s, 1H).

Step 3. 2-(A r -(Carbobenzyloxy)amino-3-methoxynaphthaIene

A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et 3 N (2.59 mL, 18.6
mmol) in anh toluene (70 mL) was stirred at room temp, for 15 min., then treated with a

10 solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The resulting mixture
was heated at 80 °C for 2 h. After cooling the mixture to room temp., benzyl alcohol (2.06
mL, 20 mmol) was added via syringe. The mixture was then warmed to 80 °C overnight. The
resulting mixture was cooled to room temp., quenched with a 10% citric acid solution, and
extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a

15 saturated NaCl solution, dried (MgS0 4 ) and concentrated under reduced pressure. The
residue was purified by column chromatography (14% EtOAc/86% hexane) to give 2-{N-
(carbobenzyloxy)amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%): l H-NMR
(DMSO-d 6 ) 5 3.89 (s s 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, 1H),
8.76 (s, 1H).

Step 4. 2-Amino-3-methoxynaphthaIene ~

A slurry of 2-(A^-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10%
Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a H 2 atm (balloon) at room temp,
overnight. The resulting mixture was filtered through Celite^ and concentrated under
25 reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder (2.40 g,

18

85%): ! H-NMR (DMSO-d 6 ) 5 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, 7=8.0
Hz, 1H), 7.56 (d, 7=8.0 Hz, 1H); EI-MS m/z 173 (M + ).

A2.

Synthesis of co-Carbamyl Anilines via Formation of a Carbamylpyridine
Followed by Nucleophilic Coupling with an Aryl Amine, Synthesis of 4-
(2-A r -Methylcarbamyl-4-pyridyIoxy)aniline

O

CI

NHMe

Step la.

Synthesis of 4-chloro-A r -methyl-2-pyridinecarboxamide via the Menisci

reaction

10 Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of
4-chloropyridine (10.0 g) in A'-methylformamide (250 mL) at room temp, was added cone.
H 2 S0 4 (3,55 mL) to generate an exotherm. To this mixture was added H 2 0 2 (30% wt in H 2 0,
17 mL) followed by FeSCWH 2 0 (0.56 g) to generate another exotherm. The resulting
mixture was stirred in the dark at room temp, for 1 h, then warmed slowly over 4 h to 45 °C.

15 When bubbling had subsided, the reaction was heated at 60 °C for 16 h. The resulting
opaque brown solution was diluted with H 2 0 (700 mL) followed by a 10% NaOH solution
(250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic
phases were washed separately with a saturated NaCl solution (3 x 150 mL), then they were
combined, dried (MgS0 4 ) and filtered through a pad of silica gel with the aid of EtOAc. The

20 resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50%
hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0 °C over 72 h to
give 4-chloro-A^-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/50%
hexane) R/0.50; ! H NMR (CDC1 3 ) 5 3.04 (d, 7=5.1 Hz, 3H), 7.43 (dd, 7=5.4, 2.4 Hz, 1H),
7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, 7=5.1 Hz, 1 H); CI-MS m/z 171 ((M+H) + ).

25

Step lb.

Synthesis of 4-chloropyridine-2-carbonyI chloride HC1 salt via picolinic

acid

19

Anhydrous DMF (6.0 mL) was slowly added to S0C1 2 (180 mL) between 40° and 50 °C.
The solution was stirred in that temperature range for 10 min. then picolinic acid (60.0 g, 487
mmol) was added in portions over 30 min. The resulting solution was heated at 72 °C
(vigorous SO2 evolution) for 16 h to generate a yellow solid precipitate. The resulting
mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200
mL. The toluene addition/concentration process was repeated twice. The resulting nearly
dry residue was filtered and the solids were washed with toluene (2 x 200 mL) and dried
under high vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chloride HCI salt as a
yellow-orange solid (92.0 g, 89%).

Anh DMF (10.0 mL) was slowly added to SOCl 2 (300 mL) at 40-48 °C. The solution was
stirred at that temp, range for 10 min., then picolinic acid (100 g, 812 mmol) was added over
30 min. The resulting solution was heated at 72 °C (vigorous SO2 evolution) for 16 h to
generate a yellow solid. The resulting mixture was cooled to room temp., diluted with
toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process
was repeated twice. The resulting nearly dry residue was filtered, and the solids were washed
with toluene (50 mL) and dried under high vacuum for 4 hours to afford 4-chloropyridine-2-
carbonyl chloride HCI salt as an off-white solid (27.2 g, 16%). This material was set aside.

The red filtrate was added to MeOH (200 mL) at a rate which kept the internal temperature
below 55 °C. The contents were stirred at room temp, for 45 min., cooled to 5 °C and treated
with Et20 (200 mL) dropwise. The resulting solids were filtered, washed with Et20 (200
mL) and dried under reduced pressure at 35 °C to provide methyl 4-chloropyridine-2-
carboxylate HCI salt as a white solid (110 g, 65%): mp 108-1 12 °C; 'H-NMR (DMSO-d 6 ) 5
3.88 (s, 3H); 7.82 (dd, 7=5.5, 2.2 Hz, 1H); 8.08 (d, 7=2.2 Hz, 1H); 8.68 (d, 7=5.5 Hz, 1H);
10.68 (br s, IH); HPLC ES-MS m/z 172 ((M+H) + ).

O

Step 2.

Synthesis of methyl 4-chloropyridine-2-carboxylate HCI salt

20

o

CI

NHMe

N

Step 3a. Synthesis of 4-chloro-A r -methyl-2-pyridinecarboxamide from methyl 4-
chloropyridine-2-carboxylate

A suspension of methyl 4-chloropyridine-2-carboxylate HC1 salt (89.0 g, 428 mmol) in
5 MeOH (75 mL) at 0 °C was treated with a 2.0 M methylamine solution in THF (1 L) at a rate
which kept the internal temp, below 5 °C. The resulting mixture was stored at 3 °C for 5 h,
then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1
L) and filtered. The filtrate was washed with a saturated NaCl solution (500 mL), dried
(Na 2 S04) and concentrated under reduced pressure to afford 4-chloro-iV-methyl-2-
10 pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43 °C; l H-NMR (DMSO-
d 6 ) 5 2.81 (s, 3H), 7.74 (dd, .7=5.1, 2.2 Hz, 1H), 8.00 (d, 7=2.2, 1H), 8.61 (d, 7=5.1 Hz, 1H),
8.85 (brd, 1H); CI-MS m/z 171 ((M+H) + ).

O

cl ^rpY^ NHMe

Step 3b. Synthesis of 4-chloro-A^methyl-2-pyridinecarboxamide from 4-
15 chloropyridine-2-carbonyl chloride

4-Chloropyridine-2-carbonyl chloride HC1 salt (7.0 g, 32.95 mmol) was added in portions to
a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0 °C.
The resulting mixture was stored at 3 °C for 4 h, then concentrated under reduced pressure.
The resulting nearly dry solids were suspended in EtOAc (100 mL) and filtered. The filtrate
20 was washed with a saturated NaCl solution (2 x 100 mL), dried (Na 2 S0 4 ) and concentrated
under reduced pressure to provide 4-chloro-A r -methyl-2-pyridinecarboxamide as a yellow,
crystalline solid (4.95 g, 88%): mp 37-40 °C.

Step 4. Synthesis of 4-(2-(A r -methylcarbamoyI)-4-pyridyIoxy)aniline

25 A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was treated with
potassium rerr-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at

21

room temp, for 2 h. The contents were treated with 4-chlorowV-methyl-2-
pyridinecarboxamide (15.0 g, 87.9 mmoi) and K 2 C0 3 (6.50 g, 47.0 mmol) and then heated at
80 °C for 8 h. The mixture was cooled to room temp, and separated between EtOAc (500
mL) and a saturated NaCl solution (500 mL). The aqueous phase was back-extracted with

5 EtOAc (300 mL). The combined organic layers were washed with a saturated NaCl solution
(4 x 1000 mL), dried (Na 2 S0 4 ) and concentrated under reduced pressure. The resulting solids
were dried under reduced pressure at 35 °C for 3 h to afford 4-(2-(A r -methylcarbamoyl)-4-
pyridyloxy)amline as a light-brown solid 17.9 g, 84%): l H-NMR (DMSO-d 6 ) 5 2.77 (d, .7=4.8
Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA'BB* quartet, 7=8.4 Hz, 4H), 7.06 (dd, J=5.5, 2.5 Hz,

10 1H), 7.33 (d, ,7=2.5 Hz, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES-MS m/z 244
((M+H) + ).

A3. General Method for the Synthesis of Anilines by Nucleophilic Aromatic

Addition Followed by Nitroarene Reduction. Synthesis of 5-(4-
Aminophenoxy)isoindoline-l,3-dione

15

O

O

Step 1. Synthesis of 5-hydroxyisoindoIine-l,3-dione

To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in cone. AcOH (25 mL) was
slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated

20 at 120 °C for 45 min., then the clear, bright yellow mixture was heated at 160 °C for 2 h. The
resulting mixture was maintained at 160 °C and was concentrated to approximately 15 mL,
then was cooled to room temp, and adjusted pH 10 with a IN NaOH solution. This mixture
was cooled to 0 °C and slowly acidified to pH 5 using a IN HCl solution. The resultant
precipitate was collected by filtration and dried under reduced pressure to yield 5-

25 hydroxyisoindoline-l,3-dione as a pale yellow powder as product (3.24 g, 72%): l H NMR
(DMSO-d 6 ) 5 7.00-7.03 (m, 2H), 7.56 (d, J=9.3Hz, 1H).

22

0 2 N

O

O

Step 2.

Synthesis of 5-(4-nitrophenoxy)isoindoline-l,3-dione

To a stirring slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 °C was added a solution
of 5-hydroxyisoindoline-l,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise. The bright
5 yellow-green mixture was allowed to return to room temp, and was stirred for 1 h, then 1-
fluoro-4-nitrobenzene (2.67 g, 18,7 mmol) was added via syringe in 3-4 portions. The
resulting mixture was heated at 70 °C overnight, then cooled to room temp, and diluted
slowly with water (150 mL), and extracted with EtOAc (2 x 100 mL). The combined organic
layers were dried (MgSC>4) and concentrated under reduced pressure to give 5-(4-

10 mtrophenoxy)isoindoline-l,3-dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc/70%
hexane) R/0.28; 1H NMR (DMSO-d 6 ) 5 7.32 (d, 7=12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89(d,
7=7.8 Hz, 1H), 8.29 (d, J=9 Hz, 2H), 1 1.43 (br s, 1H); CI-MS m/z 285 ((M+H)\ 100%).

15 A solution of 5-(4-nitrophenoxy)isoindoline-l,3-dione (0.6 g, 2.11 mmol) in cone. AcOH (12
mL) and water (0.1 mL) was stirred under stream of argon while iron powder (0.59 g, 55.9
mmol) was added slowly. This mixture stirred at room temp, for 72 h, then was diluted with
water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were
dried (MgS0 4 ) and concentrated under reduced pressure to give 5-(4-

20 aminophenoxy)isoindoline-l,3-dione as a brownish solid (0.4 g, 75%): TLC (50%
EtOAc/50% hexane) R/0.27; ! H NMR (DMSO-d 6 ) 5 5.14 (br s, 2H), 6.62 (d, 7=8.7 Hz, 2H),
6.84 (d, 7=8.7 Hz, 2H), 7.03 (d, 7=2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d, 7=8.4 Hz, 1H), 11.02
(s, 1H); HPLC ES-MS m/z 255 ((M+H)\ 100%).

25 A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis of 5-tert-

O'

Step 3.

Synthesis of 5-(4-aminophenoxy)isoindoline-l,3-dione

Butyl-2-(2,5-dimethylpyrrolyl)aniIine

23

Step 1. Synthesis of l-(4-^r^-butyl-2-nitrophenyl)-2,5-dimethylpyrrole

To a stirring solution of 2-nitro-4-ter?-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10
mL) was added AcOH (O.lmL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe. The

5 reaction mixture was heated at 120 °C for 72 h with azeotropic removal of volatiles. The
reaction mixture was cooled to room temp., diluted with CH2CI2 (10 mL) and sequentially
washed with a IN HC1 solution (15 mL), a IN NaOH solution (15 mL) and a saturated NaCl
solution (15mL), dried ( MgS0 4 ) and concentrated under reduced pressure. The resulting
orange-brown solids were purified via column chromatography (60 g SiCb; gradient from 6%

10 EtO Ac/94% hexane to 25% EtO Ac/75% hexane) to give l-(4-/err-butyl-2-nitrophenyl)-2,5-
dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtO Ac/85% hexane) R f
0.67; l H NMR (CDCI3) d 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1H), 7.62
(dd, 1H), 7.88 (d, J=2A Hz, 1H); CI-MS m/z 273 ((M+H)\ 50%).

15 Step 2. Synthesis of 5-^rN-Butyl-2-(2,5-dimethylpyrrolyl)aniIine

A slurry of l-(4-rerr-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol),
10%Pd/C (0.056 g) and EtO Ac (50 mL) under an H 2 atmosphere (balloon) was stirred for 72
h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced
pressure to give 5-/er^-butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish solids (0.30 g,
20 99%):TLC(10%EtOAc/90%hexane)R/0.43; l HNMR(CDCl 3 )5 1.28 (s,9H), 1.87-1.91
(m. 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, IH).

24

A5.

General Method for the Synthesis of Anilines from Anilines by
Nucleophilic Aromatic Substitution. Synthesis of 4-(2-(;V-
Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCI Salt

O

H 2 N

HCI

NHMe

Me

5 A solution of 4-amino-3-methylphenoi (5.45 g, 44.25 mmol) in dry dimethylacetamide (75
mL) was treated with potassium terf-butoxide (10.86 g, 96.77 mmol) and the black mixture
was stirred at room temp, until the flask had reached room temp. The contents were then
treated with 4-chloro-A r -methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2
mmol) and heated at 1 10 °C for 8 h. The mixture was cooled to room temp, and diluted with

10 water (75 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The combined
organic layers were washed with a saturated NaCl solution (200 mL), dried (MgS0 4 ) and
concentrated under reduced pressure. The residual black oil was treated with Et 2 0 (50 mL)
and sonicated. The solution was then treated with HCI (1 M in Et 2 0; 100 mL) and stirred at
room temp, for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by

15 filtration from solution and stored under anaerobic conditions at 0 °C prior to use: *H NMR
(DMSO-d 6 ) 5 2.41 (s, 3H), 2.78 (d, J=4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, .7=8.5, 2.6 Hz,
1H), 7.23 (dd, 7=5.5, 2.6 Hz, 1H), 7.26 (d, J=2.6 Hz, 1H), 7.55 (d, J=2.6 Hz, 1H), 7.64 (d,
7=8.8 Hz, 1H), 8.55 (d, 7=5.9 Hz, 1H), 8.99 (q, 7=4.8 Hz, 1H).

20 A6. General Method for the Synthesis of Anilines from Hydroxy anilines by /V-

25 Iron (3.24 g, 58.00 mmol) was added to stirring TFA (200 mL). To this slurry was added 2-
chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 mL). This gray

Protection, Nucleophilic Aromatric Substitution and Deprotection.
Synthesis of 4-(2-(A r -Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline

Step 1:

Synthesis of 3-Ch!oro-4-(2,2,2-trifluoroacetyIamino)phenol

slurry was stirred at room temp, for 6 d. The iron was filtered from solution and the

25

remaining material was concentrated under reduced pressure. The resulting gray solid was
dissolved in water (20 mL). To the resulting yellow solution was added a saturated NaHC0 3
solution (50 mL). The solid which precipitated from solution was removed. The filtrate was
slowly quenched with the sodium bicarbonate solution until the product visibly separated
from solution (determined was using a mini work-up vial).. The slightly cloudy yellow
solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed
with a saturated NaCl solution (125 mL), dried (MgSCU) and concentrated under reduced
pressure. The l H NMR (DMSO-d 6 ) indicated a 1:1 ratio of the nitrophenol starting material
and the intended product 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol. The crude material
was taken on to the next step without further purification.

NHMe

Step 2: Synthesis of ^(l-CA^-MethylcarbamoyO-^pyridyloxy^-chlorophenyl

(222-trifluoro)acetamide

A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46 mmol) in
dry dimethyl acetamide (50 mL) was treated with potassium terf-butoxide (5.16 g, 45.98
mmol) and the brownish black mixture was stirred at room temp, until the flask had cooled to
room temp. The resulting mixture was treated with 4-chloro-Af-methyl-2-
pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 °C under
argon for 4 d. The black reaction mixture was cooled to room temp, and then poured into
cold water (100 mL). The mixture was extracted with EtOAc (3 x 75 mL) and the combined
organic layers were concentrated under reduced pressure. The residual brown oil was
purified by column chromatography (gradient from 20% EtO Ac/pet. ether to 40% EtO Ac/pet.
ether) to yield 4-(2-(A r -Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-
trifluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol).

O

NHMe

Step 3. Synthesis of 4-(2-(A r -Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline

26

A solution of crude 4-(2-(^-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-
trifluoro)acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a IN
NaOH solution (20 mL). This brown solution was allowed to stir for 8 h. To this solution
was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3 x 40 mL)
5 and the solvent was concentrated to yield 4-(2-(A r -Methylcarbamoyl)-4-pyridyloxy)-2-

chloroaniline as a green oil that solidified upon standing (2.86 g, 10.30 mmol): ] H NMR
(DMSO-d 6 ) 5 2.77 (d, 7=4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, 7=8.5, 2.6 Hz, 1H), 6.76 (d,
7-2.6 Hz, 1H), 7.03 (d, 7=8.5 Hz, 1H), 7.07 (dd, 7=5.5, 2.6, Hz, 1H), 7.27 (d, 7=2.6 Hz, 1H),
8.46 (d, 7=5.5 Hz, 1H), 8.75 (q, 7=4.8, 1H).

10

A7.

General Method for the Deprotection of an Acylated Aniline. Synthesis of
4-Chloro-2-methoxy-5-(trifluoromethyl)aniline

OMe

20

15

A suspension of 3-chloro-6-(N-acetyl)-4-(trifluoromethyl)anisole (4.00 g, 14.95
mmol) in a 6M HG1 solution (24 mL) was heated at the reflux temp, for 1 h. The
resulting solution was allowed to cool to room temp, during which time it solidified
slightly. The resulting mixture was diluted with water (20 mL) then treated with a
combination of solid NaOH and a saturated NaHCC>3 solution until the solution was
basic. The organic layer was extracted with CH2CI2 (3 x 50 mL). The combined
organics were dried (MgSC>4) and concentrated under reduced pressure to yield 4-
chloro-2-methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g, 14.2 mmol): ! H
NMR (DMSO-d 6 ) 5 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).

25

A8.

General Method for Synthesis of co-Alkoxy-co-carboxyphenyl Anilines.
Synthesis of 4-(3-(A r -MethyIcarbamoIy)-4-methoxyphenoxy)aniline.

O

Step 1.

4-(3-Methoxycarbonyl-4-methoxyphenoxy)-l -nitrobenzene:

27

To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-l -nitrobenzene (prepared from 2,5-
dihydroxybenzoic acid in a manner analogous to that described in Method A13, Step 1, 12
mmol) in acetone (50 mL) was added K 2 C0 3 (5 g) and dimethyl sulfate (3.5 raL). The
resulting mixture was heated at the reflux temp, overnight, then cooled to room temp, and
filtered through a pad of Celite®. The resulting solution was concentrated under reduced
pressure, absorbed onto Si0 2 , and purified by column chromatography (50% EtOAc / 50%
hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-l -nitrobenzene as a yellow
powder (3 g): mp 115-118 °C.

o

OH

Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-l-nitrobenzene:

A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-l -nitrobenzene (1.2 g), KOH (0.33
g) and water (5 mL) in MeOH (45 mL) was stirred at room temp, overnight and then heated
at the reflux temp, for 4 h. The resulting mixture was cooled to room temp, and concentrated
under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous
mixture was made acidic with a IN HC1 solution. The resulting mixture was extracted with
EtOAc (50 mL). The organic layer was dried (MgS0 4 ) and concentrated under reduced
pressure to give 4-(3-carboxy-4-methoxyphenoxy)-l-nitrobenzene (1 .04 g).

O

^^°^r*\ NHMe

Step 3. 4-(3-(^V-MethyIcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene:

To a solution of 4-(3-carboxy-4-methoxyphenoxy)-l -nitrobenzene (0.50 g, 1.75 mmol) in
CH 2 C1 2 (12 mL) was added SOCl 2 (0.64 mL, 8.77 mmol) in portions. The resulting solution
was heated at the reflux temp, for 18 h, cooled to room temp., and concentrated under
reduced pressure. The resulting yellow solids were dissolved in CH 2 C1 2 (3 mL) then the
resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 mL, 7.02
mmol) in portions (CAUTION: gas evolution), and stirred at room temp, for 4 h. The
resulting mixture was treated with a IN NaOH solution, then extracted with CH 2 Cl 2 (25 mL).

28

10

The organic layer was dried (Na2SO.O and concentrated under reduced pressure to give 4-(3-
0V-methylcarbamoly)-4-methoxyphenoxy)-l -nitrobenzene as a yellow solid (0.50 g, 95%).

O

H 2 N" ^ ^^OMe
Step 4. 4-(3-(A^-Methylcarbamoly)-4-methoxyphenoxy)aniline:

A slurry of 4-(3-(A^-methylcarbamoly)-4-methoxyphenoxy)-l -nitrobenzene (0.78 g, 2.60
mmol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under 1 atm of H 2 (balloon) for
2.5 d, then was filtered through a pad of Celite®. The resulting solution was concentrated
under reduced pressure to afford 4-(3-(N-niethylcarbanioly)-4-methoxyphenoxy)aniline as an
off-white solid (0.68 g, 96%): TLC (0.1% Et 3 N/99.9% EtOAc) R/0.36.

A9. General Method for Preparation of co-Alkylphthalimide-containing

Anilines. Synthesis of 5-(4-Aminophenoxy)-2-methylisoindoline-l,3-dione

O

Step 1. Synthesis of 5-(4-Nitrophenoxy)-2-methylisoindoIine-l,3-dione:

15 A slurry of 5-(4-nitrophenoxy)isoindoline-l,3-dione (A3 Step 2; 1.0 g, 3.52 mmol) and NaH
(0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp, for 1 h, then treated with
methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temp,
overnight, then was cooled to °C and treated with water (10 mL). The resulting solids were
collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-methylisoindoline-

20 1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% hexane) R/0.61 .

O

o

29

Step 2. Synthesis of 5-(4-Aminophenoxy)-2-methylisoindoline-l,3-dione:

A slurry of nitrophenoxy)-2-methylisoindoline-l,3-dione (0.87 g, 2.78 mmol) and 10% Pd/C
(0.10 g) in MeOH was stirred under 1 atm of H 2 (balloon) overnight. The resulting mixture
was filtered through a pad of Celite® and concentrated under reduced pressure. The resulting
yellow solids were dissolved in EtOAc (3 mL) and filtered through a plug of Si0 2 (60%
EtOAc/40% hexane) to afford 5-(4-aminophenoxy)-2-methylisoindoline-l,3-dione as a
yellow solid (0.67 g, 86%): TLC (40% EtO Ac/60% hexane) R/0.27.

A10. General Method for Synthesis of (D-Carbamoylaryl Anilines Through

Reaction of co-Alkoxycarbonylaryl Precursors with Amines. Synthesis of
4-(2-(A r -(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline

O

Stepl. Synthesis of 4-Chloro-2-(iV-(2-morpholin-4-ylethyl)carbamoyl)pyridine

To a solution of methyl 4-chloropyridine-2-carboxylate HC1 salt (Method A2, Step 2; 1.01 g,
4.86 mmol) in THF (20 mL) was added 4-(2-aminoethyl)morpholine (2.55 mL, 19.4 mmol)
dropwise and the resulting solution was heated at the reflux temp, for 20 h, cooled to room
temp., and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50
mL). The organic layer was dried (MgS0 4 ) and concentrated under reduced pressure to
afford 4-chloro-2-(A f -(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil (1.25 g,
95%): TLC (10% MeOH/90% EtOAc) R f 0.50.

O

30

Step 2.

Synthesis of 4-(2-(A L (2-Morpholin-4-
yIethyl)carbamoyl)pyridyloxy)aniline.

A solution of 4-ammophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53 g, 4.75
mol) in DMF (8 mL) was stirred at room temp, for 2 h, then was sequentially treated with 4-

5 chloro-2-(iV-(2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol) and K 2 C0 3
(0.31 g, 2.26 mmol). The resulting mixture was heated at 75 °C overnight, cooled to room
temp., and separated between EtOAc (25 mL) and a saturated NaCl solution (25 mL). The
aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were
washed with a saturated NaCl solution (3 x 25 mL) and concentrated under reduced pressure.

10 The resulting brown solids were purified by column chromatography (58 g; gradient from
100% EtOAc to 25% MeOH/75% EtOAc) to afford 4-(2-(A^-(2-morpholin-4-
ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC (10% MeOH/90% EtOAc) R/0.32.

All. General Method for the Reduction of Nitroarenes to Arylamines.

15 Synthesis of 4-(3-Carboxyphenoxy)aniline.

A slurry of 4-(3-carboxyphenoxy)-l -nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd/C (0.50
g) in MeOH (120 mL) was stirred under an H 2 atmosphere (balloon) for 2 d. The resulting
mixture was filtered through a pad of Celite®, then concentrated under reduced pressure to
20 afford 4-(3-carboxyphenoxy)aniline as a brown solid (2.26 g, 48%): TLC (10% MeOH/90%
CH 2 C1 2 ) R f 0.44 (streaking).

A12. General Method for the Synthesis of Isoindolinone-Coqtaining Anilines.
Synthesis of 4-(l-Oxoisoindolin-5-yIoxy)aniline.

O

HO.

25

O

31

Step 1. Synthesis of 5-hydroxyisoindolin-l-one

To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was slowly
added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated at the reflux
temp, for 40 min., filtered hot, and concentrated under reduced pressure. The reaction was
5 repeated on the same scale and the combined oily residue was purified by column
chromatography (1.1 Kg Si0 2 ; gradient from 60% EtOAc/40% hexane to 25% MeOH/75%
EtOAc) to give 5-hydroxyisoindolin-l-one (3.77 g): TLC (100% EtOAc) R/0.17; HPLC ES-
MS m/z 150((M+H) + ).

o

10 Step 2. Synthesis of 4-(l-isoindolinon-5-yloxy)-l-nitrobenzene

To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0 °C was added 5-hydroxyisoindolin-l-
one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room temp,
and was stirred for 45 min., then 4-fluoro- 1 -nitrobenzene was added and then mixture was
heated at 70 °C for 3 h. The mixture was cooled to 0 °C and treated with water dropwise
15 until a precipitate formed. The resulting solids were collected to give 4-(l-isoindolinon-5-
yloxy)-l -nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) R/0.35.

jctoq-

o

Step 3. Synthesis of 4-(l-oxoisoindolin-5-yloxy)aniline

A slurry of 4-(l-isoindolinon-5-yloxy)-l -nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd/C
20 (0.20 g) in EtOH (50 mL) was stirred under an H 2 atmosphere (balloon) for 4 h, then filtered
through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford 4-(l-
oxoisoindolin-5-yloxy)aniline as a dark yellow solid: TLC (100% EtOAc) R/0.1 5.

A13. General Method for the Synthesis of co-Carbamoyl Anilines via EDCI-

25 Mediated Amide Formation Followed by Nitroarene Reduction.

Synthesis of 4-(3-A r -MethyIcarbamoylphenoxy)aniline.

32

Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-l-nitrobenzene

A mixture of 4-fluoro-l -nitrobenzene (16 mL, 150 mmol), ethyl 3 -hydroxy benzoate 25 g,
5 150 mmol) and K 2 C0 3 (41 g, 300 mmol) in DMF (125 mL) was heated at the reflux temp,
overnight, cooled to room temp, and treated with water (250 mL). The resulting mixture was
extracted with EtOAc (3 x 150 mL). The combined organic phases were sequentially washed
with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na2SC>4) and
concentrated under reduced pressure. The residue was purified by column chromatography
10 (10% EtO Ac/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-l -nitrobenzene as an oil
(38 g).

O

15 Step 2. Synthesis of 4-(3-carboxyphenoxy)-l-nitrobenzene

To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-l -nitrobenzene (5.14 g, 17.9
mmol) in a 3:1 THF/water solution (75 mL) was added a solution LiOH*H20 (1.50 g, 35.8
mmol) in water (36 mL). The resulting mixture was heated at 50 °C overnight, then cooled to
room temp., concentrated under reduced pressure, and adjusted to pH 2 with a 1M HC1
20 solution. The resulting bright yellow solids were removed by filtration and washed with
hexane to give 4-(3-carboxyphenoxy)-l -nitrobenzene (4.40 g, 95%).

O

NHMe

33

Step 3. Synthesis of 4-(3-(A'-methylcarbamoyl)phenoxy)-l-nitrobenzene

A mixture of 4-(3-carboxyphenoxy)-l -nitrobenzene (3.72 g, 14.4 mmol), EDCI-HC1 (3.63 g,
18.6 mmol), tf-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8
mU 16 mmol) in CH?C1 2 (45 mL) was stirred at room temp, for 3 d, then concentrated under
reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture
was extracted with a 1M HC1 solution (50 mL). The aqueous layer was back-extracted with
EtOAc (2 x 50 mL), The combined organic phases were washed with a saturated NaCl
solution (50 mL), dried (Na 2 S0 4 ), and concentrated under reduced pressure to give 4-(3-(A^-
methylcarbamoyl)phenoxy)-l -nitrobenzene as an oil (1.89 g).

O

NHMe

Step 4. Synthesis of 4-(3-(A r -methylcarbamoyl)phenoxy)aniline

A slurry of 4-(3-(A r -methylcarbamoyl)phenoxy)-l -nitrobenzene (1.89 g, 6.95 mmol) and 5%
Pd/C (0.24 g) in EtOAc (20 mL) was stirred under an H 2 atm (balloon) overnight. The
resulting mixture was filtered through a pad of Celite® and concentrated under reduced
pressure. The residue was purified by column chromatography (5% MeOH/95% CH 2 C1 2 ).
The resulting oil solidified under vacuum overnight to give 4-(3-(A r -
methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%).

A14. General Method for the Synthesis of ©-Carbamoyl Anilines via EDO-

Mediated Amide Formation Followed by Nitroarene Reduction.
Synthesis of 4-3-(5-Methylcarbamoyl)pyridyloxy)aniline

O

Step 1. Synthesis of 4-(3-(5-methoxycarboayl)pyridyloxy)-l-nitrobenzene

To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl 5-
hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was added to a

34

solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting
mixture was heated at 70 °C overnight, cooled to room temp., and treated with MeOH (5 mL)
followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The
organic phase was concentrated under reduced pressure. The residue was purified by column
5 chromatography (30% EtOAc/70% hexane) to afford 4-(3K5-methoxycarbonyI)pyridyloxy)-
1- nitrobenzene (0.60 g).

Step 2. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline

A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-l -nitrobenzene (0.60 g, 2.20 mmol) and
10 10% Pd/C in MeOH/EtOAc was stirred under an H 2 atmosphere (balloon) for 72 h. The
resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The
residue was purified by column chromatography (gradient from 10% EtO Ac/90% hexane to
30% EtOAc/70% hexane to 50% EtOAc/50% hexane) to afford 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): ] H NMR (CDCI3) 5 3.92 (s, 3H), 6.71 (d,
15 2H), 6.89 (d, 2H), 7.73 (, 1H), 8.51 (d, 1H), 8.87 (d, 1H).

35

solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting
mixture was heated at 70 °C overnight, cooled to room temp., and treated with MeOH (5 mL)
followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The
organic phase was concentrated under reduced pressure. The residue was purified by column
5 chromatography (30% EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)-
1 -nitrobenzene (0.60 g).

O

Step 2. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)aniIine

A slurry of 4-(3 -(5 -methoxycarbonyl)pyridyloxy)-l -nitrobenzene (0.60 g, 2.20 mmol) and
10 10% Pd/C in MeOH/EtOAc was stirred under an H 2 atmosphere (balloon) for 72 h. The
resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The
residue was purified by column chromatography (gradient from 10% EtO Ac/90% hexane to
30% EtOAc/70% hexane to 50% EtOAc/50% hexane) to afford 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): l H NMR (CDCb) 5 3.92 (s, 3H), 6.71 (d,
15 2H), 6.89 (d, 2H), 7.73 (, 1H), 8.51 (d, 1H), 8.87 (d, 1H).

solution of 4-fluoronitrobenzene (1.4 mL 7 13.1 mmol) in DMF (10 mL) and the resulting
mixture was heated at 70 °C overnight, cooled to room temp., and treated with MeOH (5 mL)
followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The
organic phase was concentrated under reduced pressure. The residue was purified by column
5 chromatography (30% EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)-
1 -nitrobenzene (0.60 g).

A slurry of 4-(3 -(5 -methoxycarbonyl)pyridyloxy)-l -nitrobenzene (0.60 g, 2.20 mmol) and
10 10% Pd/C in MeOH/EtOAc was stirred under an H 2 atmosphere (balloon) for 72 h. The
resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The
residue was purified by column chromatography (gradient from 10% EtOAc/90% hexane to
30% EtOAc/70% hexane to 50% EtOAc/50% hexane) to afford 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): ! H NMR (CDC1 3 ) 5 3.92 (s, 3H), 6.71 (d,
15 2H), 6.89 (d, 2H), 7.73 (, 1H), 8.51 (d, 1H), 8.87 (d, 1H).

O

Step 2.

Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline

35

A15. Synthesis of an Aniline via Electrophilic Nitration Followed by Reduction.
Synthesis of 4-(3-MethyIsuifamoylphenoxy)aniline.

5 To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0
°C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was
allowed to warm to room temp, and was stirred at room temp, overnight. The resulting
mixture was separated between EtOAc (25 mL) and a 1 M HC1 solution (25 mL). The
aqueous phase was back- extracted with EtOAc (2 x 25 mL). The combined organic phases

10 were sequentially washed with water (2 x 25 mL) and a saturated NaCl solution (25 mL),
dried (MgS0 4 ) and concentrated under reduced pressure to give AT-methyl-3-
bromobenzenesulfonamide as a white solid (2.8 g, 99%).

15 To a slurry of phenol (1.9 g, 20 mmol), K 2 C0 3 (6.0 g, 40 mmol), and Cul (4 g, 20 mmol) in
DMF (25 mL) was added A^methyl-S-bromobenzenesulfonamide (2.5 g, lOmmol), and the
resulting mixture was stirred at the reflux temp, overnight, cooled to room temp., and
separated between EtOAc (50 mL) and a 1 N HC1 solution (50 mL). The aqueous layer was
back-extracted with EtOAc (2 x 50 mL). The combined organic phases were sequentially

20 washed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgS0 4 ), and
concentrated under reduced pressure. The residual oil was purified by column
chromatography (30% EtOAc/70% hexane) to give 4-(3-(A r -
methylsulfamoyl)phenyloxy)benzene (0.30 g).

Step 1.

Synthesis of iV-methyl-3-bromobenzenesulfonamide

Step 2.

Synthesis of 4-(3-(A r -methylsulfamoyl)phenyIoxy)benzene

36

Step 3.

Synthesis of ^(S^-methylsulfamoyOphenyloxy)-! -nitrobenzene

To a solution of 4-(3-(A-methylsulfamoyl)phenyloxy)benzene (0.30 g, 1.14 mmol) in TFA (6
mL) at -10°C was added NaN0 2 (0.097 g, 1.14 mmol) in portions over 5 min. The resulting
solution was stirred at -10 °C for 1 h, then was allowed to warm to room temp., and was
concentrated under reduced pressure. The residue was separated between EtOAc (10 mL)
and water (10 mL). The organic phase was sequentially washed with water (10 mL) and a
saturated NaCl solution (10 mL), dried (MgS0 4 ) and concentrated under reduced pressure to
give 4-( 3 -(Af-methylsulfamoyl)phenyloxyH -nitrobenzene (0.20 g). This material carried on
to the next step without further purification.

A slurry of 4-(3-(7V-methylsulfamoyl)phenyloxy)-l -nitrobenzene (0.30 g) and 10% Pd/C
(0.030 g) in EtOAc (20 mL) was stirred under an H2 atmosphere (balloon) overnight. The
resulting mixture was filtered through a pad of Celite®. The filtrate was concentrated under
reduced pressure. The residue was purified by column chromatography (30% EtOAc/70%
hexane) to give 4-(3-(A r -methylsulfamoyl)phenyloxy)aniline (0.070 g).

A16. Modification of co-ketones. Synthesis of 4-(4-(l-(iV-

To a slurry of 4-(4-acetylphenoxy)aniline HC1 salt (prepared in a manner analogous to
Method A13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine (1.0 mL)
was added 0-methylhydroxylamine HC1 salt (0.65 g, 7.78 mmol, 2.0 equiv.). The resulting
solution was heated at the reflux temperature for 30 min, cooled to room temperature and
concentrated under reduced pressure. The resulting solids were triturated with water (10 mL)
and washed with water to give 4-(4-(l -(A^methoxy)iminoethyl) phenoxyaniline HC1 salt as a

Step 4.

Synthesis of 4-(3-(A r -methylsulfamoyl)phenyloxy)aniline

methoxy)iminoethyl)phenoxyaniline HC1 salt.

37

yellow solid (0.85 g): TLC (50% EtOAc/50% pet. ether) R/0.78; l H NMR (DMSO-d 6 ) 5 3.90
(s, 3H), 5.70 (s, 3H); HPLC-MS m/z 257 ((M+H) + ).

A17. Synthesis of 7V-(co-SilyloxyaIkyI)amides. Synthesis of 4-(4-(2-(7V-(2-

5 Triisopropylsilyloxy)ethyIcarbamoyl)pyridyIoxyaniIine.

Step 1. 4-Chloro-A^-(2-triisopropylsilyloxy)ethylpyridine-2-carboxainide

To a solution of 4-chloro-A^-(2-hydroxyethyl)pyridine-2-carboxamide (prepared in a manner
analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL). was added

10 triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12 g, 16.4 mmol,
2.2 equiv.). The resulting yellow solution was stirred for 3 h at room temp, then was
concentrated under reduced pressure. The residue was separated between water (10 mL) and
EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3x10 mL). The combined
organic phases were dried (MgS0 4 ), and concentrated under reduced pressure to afford 4-

15 chloro-2-(A r -(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide as an orange oil (2.32 g,
88%). This material was used in the next step without further purification.

Step 2. 4-(4-(2-(A r -(2-Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxy aniline

To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anh DMF (8 mL) was added
20 potassium terr-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) in one portion causing an exotherm.
When this mixture had cooled to room temperature, a solution of 4-chloro-2-(7V-(2-
triisopropylsilyloxy)ethyl)pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv.) in DMF (4 mL)
was added followed by K 2 C0 3 (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was
heated at 80 °C overnight. An additional portion of potassium ter/-butoxide (0.34 g, 3 mmol,
25 0.5 equiv.) was then added and the mixture was stirred at 80 °C an additional 4 h. The
mixture was cooled to 0 °C with an ice/water bath, then water (approx. 1 mL) was slowly
added dropwise. The organic layer was extracted with EtOAc (3x10 mL). The combined

38

organic layers were washed with a saturated NaCl solution (20 mL), dried (MgS0 4 ) and
concentrated under reduced pressure. The brown oily residue was purified by column
chromatography (Si0 2 ; 30% EtOAc/ 70% pet ether) to afford 4-(4-(2-(7V-(2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a clear light brown oil (0.99 g,
5 38%).

A18. Synthesis of 2-Pryidinecarboxylate Esters via Oxidation of 2-

Methylpyridines. Synthesis of 4-(5-(2-

methoxycarbonyl)pyridyioxy)aniline.

10

Step 1. 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenzene.

A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), l-fluoro-4-nitrobenzene (9.8
mL, 91.6 mmol, 1.0 equiv.), K 2 C0 3 (25 g, 183 mmol, 2.0 equiv.) in DMF (100 mL) was
heated at the reflux temperature overnight. The resulting mixture was cooled to room
15 temperature, treated with water (200 mL), and extracted with EtOAc (3 x 100 mL). The
combined organic layers were sequentially washed with water (2 x 100 mL) and a saturated
NaCl solution ((100 mL), dried (MgS0 4 ) and concentrated under reduced pressure to give 4-
(5 -(2-methyl)pyridyloxy)-l -nitrobenzene as a brown solid (12.3 g).

20 Step 2. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)-l-nitrobenzene.

A mixture of 4-(5-(2-methyl)pyridyloxy)-l -nitrobenzene (1.70 g, 7.39 mmol) and selenium
dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the reflux
temperature for 5 h, then cooled to room temperature. The resulting slurry was filtered , then
concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The
25 solution was treated with a cone HC1 solution (7 mL), then heated at the reflux temperature
for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue
was separated between EtOAc (50 mL) and a IN NaOH solution (50 mL). The aqueous layer
was extracted with EtOAc (2 x 50 mL). The combined organic layers were sequentially

39

washed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgS0 4 ) and
concentrated under reduced pressure. The residue was purified by column chromatography
(Si0 2 ; 50% EtOAc/50% hexane) to afford 4-(5-(2-methoxycarbonyl)pyridyloxy)-l-
nitrobenzene (0.70 g).

Step 3. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)aniline.

A slurry of 4-(5-(2-methoxycarbonyi)pyridyloxy)-l-nitrobenzene (0.50 g) and 10% Pd/C
(0.050 g) in a mixture of EtOAc (20 mL) and MeOH (5 mL) was placed under a H 2
atmosphere (balloon) overnight- The resulting mixture was filtered through a pad of Celite®,
10 and the filtrate was concentrated under reduced pressure. The residue was purified by
column chromatography (Si0 2 ; 70% EtOAc/30% hexane) to give 4-(5-(2-
methoxycarbonyl)pyridyloxy)aniline (0.40 g).

A19. Synthesis of co-Sulfonylphenyl Anilines. Synthesis of 4-(4-

1 5 Methylsulfonylphenyoxy)aniline.

Step 1. 4-(4-Methylsulfonylphenoxy)-l-nitrobenzene: To a solution of 4-(4-
methylthiophenoxy)-! -nitrobenzene (2.0 g, 7.7 mmol) in CH2CI2 (75 mL) at 0 °C was slowly
added w-CPBA (57-86%, 4.0 g), and the reaction mixture was stirred at room temperature for
20 5 h. The reaction mixture was treated with a IN NaOH solution (25 mL). The organic layer
was sequentially washed with a IN NaOH solution (25 mL), water (25 mL) and a saturated
NaCl solution (25 mL), dried (MgS0 4 ), and concentrated under reduced pressure to give 4-
(4-methylsulfonylphenoxy)-l -nitrobenzene as a solid (2.1 g).

25 Step 2. 4-(4-MethylsulfonyIphenoxy)-l-aniline: 4-(4-Methylsulfonylphenoxy)- 1 -
nitrobenzene was reduced to the aniline in a manner analogous to that described in Method
A 18, step 3.

40

B- Synthesis of Urea Precursors

Bl. General Method for the Synthesis of Isocyanates from Anilines Using

CDI. Synthesis of 4-Bromo-3-(trifluoromethyl)phenyl Isocyanate.

5 Step 1. Synthesis of 4-bromo-3-(trifluoromethyI)aniline HC1 salt

To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 267 mmol) in Et 2 0 (500 mL) was
added an HC1 solution (1 M in Et 2 0; 300 mL) dropwise and the resulting mixture was stirred
at room temp, for 16 h. The resulting pink- white precipitate was removed by filtration and
washed with Et 2 0 (50 mL) and to afford 4-bromo-3-(trifluoromethyl)aniline HCl.salt (73 g ,
10 98%).

CF 3

Br.

*NCO

Step 2. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate

A suspension of 4-bromo-3-(trifluoromethyl)aniline HC1 salt (36.8 g, 133 mmol) in toluene
15 (278 mL) was treated with trichloromethyl chloro formate dropwise and the resulting mixture
was heated at the reflux temp, for 18 h. The resulting mixture was concentrated under
reduced pressure. The residue was treated with toluene (500 mL), then concentrated under
reduced pressure. The residue was treated with CH 2 C1 2 (500 mL), then concentrated under
reduced pressure. The CH 2 C1 2 treatment/concentration protocol was repeated and resulting
20 amber oil was stored at -20 °C for 16 h, to afford 4-bromo-3-(trifluoromethyl)phenyl
isocyanate as a tan solid (35.1 g, 86%): GC-MS m/z 265 (M + ).

C. Methods of Urea Formation

CI a. General Method for the Synthesis of Ureas by Reaction of an Isocyanate

25 with an Aniline. Synthesis of ^-(^Chloro-S^trifluoromethyOphenyO-TV -

(4-(2-(/V-methylcarbamoyl)-4-pyridyIoxy)phenyl) Urea

41

NHMe

H H

A solution of 4-ch1oro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90 mmol) in CH 2 C1 2
(35 mL) was added dropwise to a suspension of 4-(2-(A r -methylcarbamoyl)-4-
pyridyloxy)aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH 2 C1 2 (35 mL) at 0 °C. The

5 resulting mixture was stirred at room temp, for 22 h. The resulting yellow solids were
removed by filtration, then washed with CH 2 C1 2 (2 x 30 mL) and dried under reduced
pressure (approximately 1 mmHg) to afford ^V-(4-chloro-3-(trifluoromethyl)phenyl)-A^ '-(4-( 2-
(A r -methylcarbamoyl)-4-pyridyloxy)phenyl) urea as an off-white solid (28.5 g, 93%): mp
207-209 °C; 'H-NMR (DMSO-d 6 ) 5 2.77 (d, 7=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, 7-2.5 Hz,

10 1H), 7.62 (m, 4H), 8.11 (d, 7=2.5 Hz, 1H), 8.49 (d, 7=5.5 Hz, IH), 8.77 (br d, 1H), 8.99 (s,
1H), 9.21 (s, 1H); HPLC ES-MS m/z 465 ((M+H) + ).

Clb. General Method for the Synthesis of Ureas by Reaction of an Isocyanate

with an Aniline. Synthesis of AH4-Bromo-3-(trifluoromethyl)phenyl)-A^
15 (4-(2-(A r -methyIcarbamoyl)-4-pyridyIoxy)phenyl) Urea

NHMe

H H

A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method Bl, Step 2; 8.0 g, 30.1
mmol) in CH 2 C1 2 (80 mL) was added dropwise to a solution of 4-(2-(7V-methylcarbamoyl)-4-
pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH 2 C1 2 (40 mL) at 0 °C. The
20 resulting mixture was stirred at room temp, for 16 h. The resulting yellow solids were
removed by filtration, then washed with CH 2 C1 2 (2 x 50 mL) and dried under reduced
pressure (approximately 1 mmHg) at 40 °C to afford 7V-(4-bromo-3-(trifluoromethyl)phenyl)-
/ V'-(4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a pale-yellow solid (13.2 g,

90%): mp 203-205 °C; 1 H-NMR (DMSO-d 6 ) 5 2.77 (d,>4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d,
25 7=2.5 Hz, 1H), 7.58 (m, 3H), 7.77 (d, 7=8.8 Hz, 1H), 8.11 (d, 7=2.5 Hz, 1H), 8.49 (d, 7=5.5
Hz, IH), 8.77 (brd, IH), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 509 ((M+H)").

42

Clc.

General Method for the Synthesis of Ureas by Reaction of an Isocyanate
with an Aniline. Synthesis of yV-(4-Chloro-3-(trifluoromethyl)phenyl)-A^ , -
(2-methyl-4-(2-(N-methyIcarbamoyl)(4-pyridyioxy))phenyI) Urea

9 F 3

o

ci

Me

NHMe

5 A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))aniline (Method A5; 0. 1 1 g,
0.45 mmol) in CH 2 C1 2 (1 mL) was treated with Et 3 N (0.16 mL) and 4-chloro-3-
(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was
stirred at room temp, for 6 d, then was treated with water (5 mL). The aqueous layer was
back-extracted with EtOAc (3x5 mL). The combined organic layers were dried (MgS0 4 )

10 and concentrated under reduced pressure to yield A r -(4-chloro-3-(trifluoromethyl)phenyl)-A^'-
(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea as a brown oil (0.11 g, 0.22
mmol): ] H NMR (DMSO-d 6 ) 5 2.27 (s, 3H), 2.77 (d, 7=4.8 Hz, 3H), 7.03 (dd, 7=8.5, 2.6 Hz,
1H), 7.11 (d, 7=2.9 Hz, 1H), 7.15 (dd, 7=5.5, 2.6, Hz, 1H), 7.38 (d, 7=2.6 Hz, 1H), 7.62 (app
d, 7=2.6 Hz, 2H), 7.84 (d, 7=8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H); 8.50 (d, 7=5.5 Hz, 1H),

15 8.78 (q, 7=5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479 ((M+H) + ).

Cld. General Method for the Synthesis of Ureas by Reaction of an Isocyanate

To, a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3 mmol) in
CH2CI2 (308 mL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one part. The
resulting mixture was stirred at room temp, for 1 h, treated with CH2CI2 (100 mL), and
concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture
25 of EtOAc (110 mL) and MeOH (15mL), and the clear solution was washed with a 0.05 N
HC1 solution. The organic layer was concentrated under reduced pressure to afford impure

with an Aniline. Synthesis of A^-ChloroO^trifluoromethy^phenyO-iV'-
(4-aminophenyl) Urea

20

H

H

43

Ar-(4-chloro-3-(trifluoromethyl)phenyl)-/^'-(4-aminopheny0 urea (3.3 g): TLC (100%
EtOAc) R/0.72.

5

Cle.

General Method for the Synthesis of Ureas by Reaction of an Isocyanate
with an Aniline. Synthesis of A^-(4-Chloro-3-(trifluoromethyl)phenyl)wV-
(4-ethoxycarbonylphenyl) Urea

CF 3

O

CI

OEt

To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH 2 C1 2 (30 mL) was
added 4-chloro-3-(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the solution was stirred at
10 room temp, overnight. The resulting slurry was diluted with CH2CI2 (50 mL) and filtered to
afford iV-(4-chloro-3-(trifluoromethyl)phenyl)-A r '-(4-ethoxycarbonylphenyl) urea as a white
solid (5.93 g, 97%): TLC (40% EtOAc/60% hexane) R/0.44.

Clf. General Method for the Synthesis of Ureas by Reaction of an Isocyanate

15 with an Aniline. Synthesis of A r -(4-ChIoro-3-(trifluoromethyl)phenyl)-A r -

To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.21g, 5.46 mmol) in CH 2 C1 2
(8 mL) was added 4-(3-carboxyphenoxy)aniline (Method All; 0.81 g, 5.76 mmol) and the
20 resulting mixture was stirred at room temp, overnight, then treated with MeOH (8 mL), and
stirred an additional 2 h. The resulting mixture was concentrated under reduced pressure.
The resulting brown solids were triturated with a 1:1 EtOAc/hexane solution to give W-(4-
chloro-3-(trifluoromethyl)phenyl)-iV '-(3-carboxyphenyl) urea as an off-white solid (1.21 g,
76%).

(3-carboxyphenyl) Urea

CF 3

C2a.

General Method for Urea Synthesis by Reaction of an Aniline with V tJ V-
Carbonyl Ditmidazole Followed by Addition of a Second Aniline.

44

Synthesis of ^-(Z-Methoxy-S-CtrifluoromethyOphenylVA'^^I-^V-
methyIcarbamoyl)-4-pyridyloxy)phenyl) Urea

To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CH 2 C1 2 (15 mL) at 0 °C
5 was added CDI (0.13 g). The resulting solution was allowed to warm to room temp, over 1 h,
was stirred at room temp, for 16 h, then was treated with 4-(2-(A r -methylcarbamoyl)-4-
pyridyloxy)aniline (0.18 g). The resulting yellow solution was stirred at room temp, for 72 h,
then was treated with H 2 0 (125 mL). The resulting aqueous mixture was extracted with
EtOAc (2 x 150 mL). The combined organics were washed with a saturated NaCl solution
10 (100 mL), dried (MgS0 4 ) and concentrated under reduced pressure. The residue was
triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration
and washed with EtOAc. The filtrate was concentrated under reduced pressure and the
residual oil purified by column chromatography (gradient from 33% EtOAc/67% hexane to
50% EtOAc/50% hexane to 100% EtOAc) to give A^-(2-methoxy-5-(trifluoromethyl)phenyl)-
15 A r '-(4-(2-(A^-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a light tan solid (0.098 g, 30%):
TLC (100% EtOAc) R/0.62; l H NMR (DMSO-ck) 5 2.76 (d, J=4.8 Hz, 3H), 3.96 (s, 3H),
7.1-7.6 and 8.4-8.6 (m, 11H), 8.75 (d, */=4.8 Hz, 1H), 9.55 (s, 1 H); FAB-MS m/z 461
((M+H) + ).

20 C2b. General Method for Urea Synthesis by Reaction of an Aniline with N,N f -

Carbonyl Diimidazole Followed by Addition of a Second Aniline.
Symmetrical Urea's as Side Products of a AyV'-Carbonyl Diimidazole
Reaction Procedure. Synthesis of Bis(4-(2-(A r -methylcarbamoyl)-4-
pyridyloxy)phenyl) Urea

25

45

To a stirring solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH2CI2 (15 mL)
at 0 C was added CDI (0.13 g). The resulting solution was allowed to warm to room temp,
over 1 h then was stirred at room temp, for 16 h. The resulting mixture was treated with 4-(2-
(A r -methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yellow solution stirred at

5 room temp, for 72 h, then was treated with water (125 mL). The resulting aqueous mixture
was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with a
saturated NaCl solution (100 ml), dried (MgS0 4 ) and concentrated under reduced pressure.
The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were
collected by filtration and washed with EtOAc to give bis(4-(2-(iV-methylcarbamoyl)-4-

10 pyridyloxy)phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) R/0.50; ! H NMR (DMSO-d 6 ) S
2.76 (d, 7=5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J=5.4 Hz, 1H), 8.75 (d, J=4.8 Hz, 2H),
8.86 (s, 2H); HPLC ES-MS m/z 513 ((M+H) + ).

C2c. General Method for the Synthesis of Ureas by Reaction of an Isocyanate

15 with an Aniline. Synthesis of 7V-(2-Methoxy-5-(trifluoromethyI)phenyl-A ^, -

(4-(l,3-dioxoisoindoIin-5-yloxy)phenyl) Urea

To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47 mmol)
in CH 2 C1 2 (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-l,3-dione (Method A3, Step

20 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12 h, then was
treated with CH 2 C1 2 (10 mL) and MeOH (5 mL). The resulting mixture was sequentially
washed with a IN HO" solution (15 mL) and a saturated NaCl solution (15 mL), dried
(MgS0 4 ) and concentrated under reduced pressure to afford A/"-(2-methoxy-5-
(trifluoromethyl)phenyl-A/"-(4-(l,3-dioxoisoindolin-5-yloxy)phenyl) urea as a white solid (0.2

25 g, 96%): TLC (70% EtOAc/30% hexane) R/0.50; l H NMR (DMSO-d 6 ) 5 3.95 (s, 3H), 7.31-
7.10 (m, 6H), 7.57 (d, J=9.3Hz, 2H), 7.80 (d, J=8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H),
11.27(brs, 1H); HPLC ES-MS 472.0 ((M+H)*, 100%).

46

C2d. General Method for Urea Synthesis by Reaction of an Aniline with N,N'-

Carbonyl Diimidazole Followed by Addition of a Second Aniline.
Synthesis of A r -(5-(^-Butyl)-2-(2,5-dimethylpyrrolyI)phenyl)wV , -(4-(2-
(Af-methyIcarbamoyl)-4-pyridyIoxy)phenyl) Urea

To a stirring solution of CDI (0.21g, 1.30 mmol) in CH 2 C1 2 (2 mL) was added 5-(fer/-butyl)-
2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one portion. The
resulting mixture was stirred at room temp, for 4 h, then 4-(2-(A r -methylcarbamoyl)-4-
pyridyloxy)aniline (0.065 g, 0.267mmol) was then added in one portion. The resulting

10 mixture was heated at 36 °C overnight, then cooled to room temp, and diluted with EtOAc (5
mL). The resulting mixture was sequentially washed with water (15 mL) and a IN HC1
solution (15mL), dried (MgS0 4 ), and filtered through a pad of silica gel (50 g) to afford yV-(5-
(^r/-butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-A r -(4-(2-(iV-methylcarbamoyl)-4-
pyridyloxy)phenyl) urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc/60% hexane)

15 R/0.24; l H NMR (acetone-d*) 5 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J=4.8Hz, 3H), 5.83 (s,
2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J=5.4Hz, 1H), 8.57 (d,
7=2.1Hz, 1H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M+H) + , 100%).

C3. Combinatorial Method for the Synthesis of Diphenyl Ureas Using

20 Triphosgene

One of the anilines to be coupled was dissolved in dichloroethane (0.10 M). This solution
was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a
bis(trichloromethyl) carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.),
followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The vial
25 was capped and heat at 80 °C for 5 h, then allowed to cool to room temp for approximately
10 h. The second aniline was added (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv.), followed
by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting

47

mixture was heated at 80 °C for 4 h, cooled to room temperature and treated with MeOH (0.5
mL). The resulting mixture was concentrated under reduced pressure and the products were
purified by reverse phase HPLC.

5 C4. General Method for Urea Synthesis by Reaction of an Aniline with Phosgene
Followed by Addition of a Second Aniline. Synthesis of A^-(2-Methoxy-5-
(trifluoromethyl)phenyl)-iV , -(4-(2-(iV-niethylcarbamoyl)-4-pyridyIoxy)phenyl) Urea

To a stirring solution of phosgene (1.9 M in toluene; 2.07 mL0.21g, 1.30 mmol) in CH2CI2
10 (20 mL) at 0 °C was added anh pyridine (0.32 mL) followed by 2-methoxy-5-
(trifluoromethyl)aniline (0.75 g). The yellow solution was allowed to warm to room temp
during which a precipitate formed. The yellow mixture was stirred for 1 h, then concentrated
under reduced pressure. The resulting solids were treated with anh toluene (20 mL) followed
by 4-(2-(A r -methylcarbamoyl)-4-pyridyloxy)aniline (prepared as described in Method A2;
15 0.30 g) and the resulting suspension was heated at 80 °C for 20 h, then allowed to cool to
room temp. The resulting mixture was diluted with water (100 mL), then was made basic
with a saturated NaHC0 3 solution (2-3 mL). The basic solution was extracted with EtOAc (2
x 250 mL). The organic layers were separately washed with a saturated NaCl solution,
combined, dried (MgSC>4), and concentrated under reduced pressure. The resulting pink-
20 brown residue was dissolved in MeOH and absorbed onto SiC>2 (100 g). Column
chromatography (300 g Si0 2 ; gradient from 1% Et 3 N/33% EtO Ac/66% hexane to 1%
Et 3 N/99% EtO Ac to 1% Et 3 N/20% MeOH/79% EtO Ac) followed by concentration under
reduced pressure at 45 °C gave a warm concentrated EtO Ac solution, which was treated with
hexane (10 mL) to slowly form crystals of A^-(2-methoxy-5-(trifluoromethyl)phenyl)-A /,, -(4-

25 (2-(A^methylcarbamoyl)-4-pyridyloxy)phenyl) urea (0.44 g): TLC (1% Et 3 N/99% EtOAc) R/
0.40.

48

D.

Iaterconversion of Ureas

Dla.

Conversion of co-Aminophenyl Ureas into co-(Aroylamino)phenyl Ureas.
Synthesis of A r -(4-Chloro-3-((trifluoromethyl)phenyl)-A r, -(4-(3-
methoxycarbonylphenyl)carboxyaminophenyl) Urea

Cl

OMe

5

H H

To a solution of 7V-(4-chloro-3 -((trifluoromethyl)phenyl)- J ?V , -(4-aminophenyl) urea (Method
Cld; 0.050 g, 1.52 mmol), mono-methyl isophthalate (0,25 g, 1.38 mmol), HOBT-H 2 0 (0.41
g, 3.03 mmol) and A^methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was added
EDCI »HC1 (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temp, overnight,

10 diluted with EtOAc (25 mL) and sequentially washed with water (25 mL) and a saturated
NaHC03 solution (25 mL). The organic layer was dried (Na 2 SC>4) and concentrated under
reduced pressure. The resulting solids were triturated with an EtOAc solution (80%
EtOAc/20% hexane) to give A r -(4-chloro-3-((trifluoromethyl)phenyl)-A^'-(4-(3-
methoxycarbonylphenyl)carboxyaminophenyl) urea (0.27 g, 43%): mp 121-122; TLC (80%

15 EtO Ac/20% hexane) R/ 0.75.

Dlb. Conversion of <o-Carboxyphenyl Ureas into co-(AryicarbamoyI)phenyI

To a solution of A^-(4-chloro-3-((trifluoromethyl)phenyl)-A/ r, -(4-(3-methylcarbamoylphenyl)
carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53
mmol), HOBT»H 2 0 (0.14 g, 1.07 mmol), and A^-methylmorpholine (0.5mL, 1.07 mmol) in
DMF (3 mL) at 0 °C was added EDCI*HC1 (0.10 g, 0.53 mmol). The resulting mixture was
25 allowed to warm to room temp, and was stirred overnight. The resulting mixture was treated
with water (lOmL), and extracted with EtOAc (25 mL). The organic phase was concentrated

Ureas, Synthesis of 7V-(4-Chloro-3-((trifluoromethyI)phenyl)-A r, -(4-(3-
methylcarbamoylphenyl)carbamoylphenyI) Urea

20

H

H

49

under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) then
filtered through a pad of silica gel (17 g, gradient from 70% EtOAc/30% hexane to 10%
MeOH/90% EtOAc) to give A r -(4-chloro-3-((trifluoromethyl)phenyl)-?/^(4-(3-
methylcarbamoylphenyl)carbamoylphenyl) urea as a white solid (0.097 g, 41%): mp 225-
5 229; TLC (100% EtOAc) R/0.23.

Die. Combinatorial Approach to the Conversion of co-Carboxyphenyl Ureas

into co-(AryicarbamoyI)phenyl Ureas, Synthesis of J /V-(4-Chloro-3-
((trifluoromethyOphenyO-A^^-CN-CS-CN-CS-
10 pyridyl)carbamoyl)phenyl)carbamoyl)phenyi) Urea

H H

A mixture of A r -(4-chloro-3-((trifluoromethyl)phenyl)-A^ J -(3-carboxyphenyl) urea (Method
Clf; 0.030 g, 0.067 mmol) and iV-cyclohexyl-A^'-(methylpolystyrene)carbodiimide (55 mg) in

15 1 ,2-dichloroethane (1 mL) was treated with a solution of 3-aminopyridine in CH2CI2 (1 M;
0.074 mL, 0.074 mmol). (In cases of insolubility or turbidity, a small amount of DMSO was
also added.) The resulting mixture was heated at 36 °C overnight. Turbid reactions were then
treated with THF (1 mL) and heating was continued for 18 h. The resulting mixtures were
treated with poly(4-(isocyanatomethyl)styrene) (0.040 g) and the resulting mixture was

20 stirred at 36 °C for 72 h, then cooled to room temp, and filtered. The resulting solution was
filtered through a plug of silica gel (1 g). Concentration under reduced pressure afforded A r -
(4-chloro-3-((trifluoromethyl)phenyl)-A^ , -(4-(N-(3-(N-(3-

pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70% EtOAc/30%
hexane) R/ 0.1 2.

25

D2. Conversion of co-Carboalkoxyaryl Ureas into co-Carbamoylaryl Ureas.

Synthesis of A r -(4-Chloro-3-((trifluoromethyl)phenyl)-A^ , -(4-(3-
methyIcarbamoylphenyl)carboxyaminophenyl) Urea

50

CI

NHMe

To a sample of A r -(4-chloro-3-((trifluoromethyl)phenyl)-A r -(4-(3-carbomethoxyphenyl)
carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 1 mL,
1.7 mmol) and the resulting mixture was stirred at room temp, overnight, then concentrated
under reduced pressure to give A r -(4-chloro-3-((trifluoromethyl)phenyl)-A r -(4-(3-
methylcarbamoylphenyl)carboxyaminophenyl) urea as a white solid: mp 247; TLC (100%
EtOAc)R/0.35.

D3. Conversion of co-Carboalkoxyaryl Ureas into co-Carboxyaryl Ureas,

To a slurry of A^-(4-chloro-3-((trifluoromethyl)phenyl)-iV -(4-ethoxycarbonyiphenyl) urea
(Method Cle; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOH solution
(2 5 N, 10 mL, 23 mmol). The resulting mixture was heated at the reflux temp, for 12 h,
cooled to room temp., and concentrated under reduced pressure. The residue was diluted
with water (50 mL), then treated with a 1 N HC1 solution to adjust the pH to 2 to 3. The
resulting solids were collected and dried under reduced pressure to give A^-(4-chloro-3-
((trifluoromethyl)phenyl)-iV , -(4-carboxyphenyl) urea as a white solid (5.05 g, 92%).

D4. General Method for the Conversion of co-AIkoxy Esters into co-Alkyl Amides.
Synthesis of 7V-(4-Chloro-3-((trifluoromethyl)phenyl)-A r, -((4-(3-(5-(2-
dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) Urea

Synthesis of A^-(4-Chloro-3-((trifIuoromethyl)phenyI)-A r, -(4-
carboxyphenyl) Urea

H

H

H

H

51

Step 1. Synthesis of ^-(^Chloro-S-CtrifluoromethyOphcnyO-iV'-tt^a^S-

carboxypyridyl) oxyphenyl) Urea

^(4-Chloro^-(trifluorom^

urea was synthesized from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4-(3-(5-
5 methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) in a manner analogous to Method
C 1 a. A suspension of A^-(4-chloro-3-(trifluoromethyl)phenyl)-A r '-((4-(3-(5-

methoxycarbonylpyridyl)oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated
with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and was stirred at room temp, for

1 h. The resulting mixture was adjusted to pH 5 with a 1 N HC1 solution. The resulting
10 precipitate was removed by filtration and washed with water. The resulting solids were

dissolved in EtOH (10 mL) and the resulting solution was concentrated under reduced
pressure. The EtOH/concentration procedure was repeated twice to give A r -(4-chloro-3-
(trifluoromethyl)phenyl)-7V -((4-(3-(5-carboxypyridyl) oxyphenyl) urea (0.18 g, 71%).

H H

15 Step 2, Synthesis of A^(4-chIoro-3-(trifluoromethyl)phenyl)-A r, -((4-(3-(5-(2-

dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea

A mixture of AA-(4-chloro-3-(trifluoromethyl)phenyl)-A^ , -((4-(3-(5-

carboxypyridyl)oxyphenyl) urea (0.050 g, 0.011 mmol), A^-dimethylethylenediamine (0.22
mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N-me thy lmorpho line (0.035 g, 0.28 mmol),
20 and EDCI'HCl (0.032 g, 0.17 mmol) in DMF (2.5 mL) was stirred at room temp, overnight.
The resulting solution was separated between EtOAc (50 mL) and water (50 mL). The
organic phase was washed with water (35 mL), dried (MgS0 4 ) and concentrated under
reduced pressure. The residue was dissolved in a minimal amount of CH 2 C1 2 (approximately

2 mL). The resulting solution was treated with Et 2 0 dropwise to give iV-(4-chloro-3-
25 (trifluoromethyl)phenyl)-A^ J ^(4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl)

urea as a white precipitate (0.48 g, 84%: l H NMR (DMSO-d 6 ) 5 2.10 s, 6H), 3.26 (s, H), 7.03
(d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, 1H), 8.43 (s, 1H) } 8.58 (t, 1H), 8.69 (s, I H), 8.90
(s, lH),9.14(s, 1H); HPLC ES-MS 522 ((M+H) + ).

52

D5. General Method for the Deprotection of AKco-Silyloxyalkyl)amides,

Synthesis of 7V-(4-Chloro-3-((trinuoromethyl)phenyl)-A r, -(4-(4-(2-(iV-(2-
hydroxy)ethy!carbamoyl)pyridyloxyphenyl) Urea.

H H

5 To a solution of Ar-(4-chloro-3-((trifluoromethyl)phenyl)-,/V '-(4-(4-(2-(tf-(2-
triisopropylsilyloxy) ethylcarbamoyl)pyridyloxyphenyl) urea (prepared in a manner
analogous to Method CI a; 0.25 g, 0.37 mmol) in anh THF (2 mL) was tetrabutylammonium
fluoride (1.0 M in THF; 2 mL). The mixture was stirred at room temperature for 5 min, then
was treated with water (10 mL). The aqueous mixture was extracted with EtOAc (3 x 10

10 mL). The combined organic layers were dried (MgS0 4 ) and concentrated under reduced
pressure. The residue was purified by column chromatography (Si02; gradient from 100%
hexane to 40% EtO Ac/60% hexane) to give iV-(4-chloro-3-((trifluoromethyl)phenyl)-AT'-(4-
(4-(2-(A^-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea as a white solid (0.019 g, 10%).

15 Listed below are compounds listed in the Tables below which have been synthesized

according to the Detailed Experimental Procedures given above:

Syntheses of Exemplified Compounds

(see Tables for compound characterization)

20

Entry 1: 4-(3-A r -Methylcarbamoylphenoxy)aniline was prepared according to Method A13.
According to Method C3, 3-terr-butylaniline was reacted with bis(trichloromethyl)carbonate
followed by 4-(3-A r -Methylcarbamoylphenoxy)aniline to afford the urea.

25 Entry 2: 4-Fluoro-l -nitrobenzene and p-hydroxyacetophenone were reacted according to
Method A 13, Step 1 to afford the 4-(4-acetylphenoxy)-l -nitrobenzene. 4-(4-Acetylphenoxy)-
1 -nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-
acetylphenoxy)aniline. According to Method C3, 3-/erf-butylaniline was reacted with
bis(trichloromethyl) carbonate followed by 4-(4-acetyIphenoxy)aniline to afford the urea.

53

Entry 3: According to Method C2d, 3-terr-butylaniline was treated with CDI, followed by 4-
(3-7V-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to
Method A8, to afford the urea.

5 Entry 4: 5-ferr-Butyl-2-methoxyaniline was converted to 5-terf-butyl-2-methoxyphenyl
isocyanate according to Method Bl. 4-(3-AT-Methylcarbamoylphenoxy)aniline, prepared
according to Method A13, was reacted with the isocyanate according to Method Cla to
afford the urea.

10 Entry 5: According to Method C2d, 5 -ferr-butyl-2-methoxy aniline was reacted with CDI
followed by 4-(3-A r -methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared
according to Method A8, to afford the urea.

Entry 6: 5-(4-Aminophenoxy)isoindoline-l,3-dione was prepared according to Method A3.
15 According to Method 2d, 5-rerr-butyl-2-methoxyaniline was reacted with CDI followed by 5-
(4-aminophenoxy)isoindoline-l,3-dione to afford the urea.

Entry 7: 4-(I-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method A12.
According to Method 2d, 5-terr-butyl-2-methoxyaniline was reacted with CDI followed by 4-
20 (l-oxoisoindolin-5-yloxy)aniline to afford the urea.

Entry 8: 4-(3-iV-Methylcarbamoylphenoxy)aniline was synthesized according to Method
A13. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI
followed by 4-(3wV-methylcarbamoylphenoxy)aniline to afford the urea.

25

Entry 9: 4-Hydroxyacetophenone was reacted with 2-chloro-5-nitropyridine to give 4-{4-
acetylphenoxy)-5-nitropyridine according to Method A3, Step 2. According to Method A8,
Step 4, 4-(4-acetylphenoxy)-5-nitropyridine was reduced to 4-(4-acetylphenoxy)-5-
aminopyridine. 2-Methoxy-5-(trifluoromethyl)aniline was converted to 2-methoxy-5-

30 (trifluoromethyl)phenyl isocyanate according to Method Bl. The isocyanate was reacted
with 4-(4-acetylphenoxy)-5-aminopyridine according to Method Cla to afford the urea.

54

Entry 10: 4-Fluoro-l -nitrobenzene and /?-hydroxyacetophenone were reacted according to
iMethod A13, Step 1 to afford the 4-(4-acetylphenoxy)-l -nitrobenzene. 4-(4-Acetylphenoxy)-
1 -nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-
acetylphenoxy)aniline. According to Method C3, 5-(trifluoromethyl)-2-methoxybutylaniline
5 was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to
afford the urea.

Entry 1 1 : 4-Chloro-A^-methyl-2-pyridinecarboxamide, which was synthesized according to
Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 using
10 DMAC in place of DMF to give 3-(-2-(iV-methylcarbamoyl)-4-pyridyloxy)aniline, According
to Method C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by
3-(-2-(A r -methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

Entry 12: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia
15 according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-
pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 using
DMAC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method
C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(2-
carbamoyi-4-pyridyloxy)aniline to afford the urea.

20

Entry 13: 4-Chloro-A r -methyl-2-pyridinecarboxamide was synthesized according to Method
A2, Step 3b. 4-Chloro-Af-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol
according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(jV-
methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-
25 (tnfluoromethyl)aniline was reacted with CDI followed by 4-(2-(A^methylcarbamoyl)-4-
pyridyloxy)aniline to afford the urea.

Entry 14: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia
according to Method A2, Step 3b to form 4-chloro-2-pyridinecarbox amide. 4-Chloro-2-
30 pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using
DMAC in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method

55

C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 4-(2-
carbamoyl-4-pyridyloxy)aniline to afford the urea.

Entry 15: According to Method C2d, 5-(triflouromethyl)-2-methoxyaniline was reacted with
CDI followed by 4-(3-A r -methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been
prepared according to Method A8, to afford the urea.

Entry 16: 4-(2-(A r -Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized
according to Method A5. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method BL The isocyanate was
reacted with 4-(2-(AA-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according to Method
Clc to afford the urea.

Entry 17: 4-(2-(iV-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized
according to Method A6. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(A r -methylcarbamoyl)-
4-pyridyloxy)-2-chloroaniline according to Method CI a to afford the urea.

Entry 18: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-
chloro-A r -methyl-2-pyridinecarboxamide, which had been synthesized according to Method
A2, Step 3b, to give 3-(2-(A^-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. 5-
(Tri£luoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl
isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was
reacted with 3-(2-(A r -methylcarbamoyl)-4-pyridyloxy)-4-methylaniline according to Method
C 1 a to afford the urea.

Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to
Method A2, Step 3b. The resulting 4-chloro-A^ethyl-2-pyridinecarboxamide was reacted
with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(vV-ethylcarbamoyl)-4-
pyridyloxy)aniline. 5-(TrifIuoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-

56

2-methoxyphenyl isocyanate was reacted with 4-(2-(A^-ethylcarbamoyl)-4-pyridyloxy)aniline
according to Method C 1 a to afford the urea.

Entry 20: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-
5 chloro-iV-methyl-2-pyridinecarboxamide, which had been synthesized according to Method
A2, Step 3b, to give 4-(2-(A r -methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl
isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was
reacted with 4-(2-(A r -methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline according to Method
10 C 1 a to afford the urea.

Entry 21: 4-(4-Methy lthiophenoxy)- 1 -nitrobenzene was oxidized according to Method A19,
Step 1 to give 4-(4-methylsulfonylphenoxy)-l -nitrobenzene. The nitrobenzene was reduced
according to Method A 19, Step 2 to give 4-(4-methylsulfonylphenoxy)-l -aniline. According
15 to Method CI a, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-
methylsulfonylphenoxy)-l -aniline to afford the urea.

Entry 22: 4-(3-carbamoylphenoxy)-l -nitrobenzene was reduced to 4-(3-

carbamoylphenoxy)aniline according to Method A15, Step 4. According to Method CI a, 5-
20 (trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-
carbamoylphenoxy)aniline to afford the urea.

Entry 23: 5-(4-Aminophenoxy)isoindoline-l,3-dione was synthesized according to Method
A3. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
25 methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl
isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-l,3-dione according to Method
Cla to afford the urea.

Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according
30 to Method A2, Step 3b. The resulting 4-chloro-MA r -dimethyl-2-pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(iV,:V-
dimethylcarbamoyI)-4-pyndyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was

57

T

converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(7V,/V-
dimethylcarbamoyl)-4-pyridyloxy)aniline according to Method Cla to afford the urea.

5 Entry 25: 4-(l-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method A12. 5-
(Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4-(l-oxoisoindolin-5-
yloxy)aniline according to Method C2d to afford the urea.

Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to
10 Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was
reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was
converted to the 4-(4-(l-(Af-methoxy)iminoethyl)phenoxy aniline HC1 salt according to
Method A 16. 5-(Trifluoromethyl)-2-methoxy aniline was converted into 5-(trifluoromethyl)-
2-methoxyphenyl isocyanate according to Method BL 5-(Trifluoromethyl)-2-methoxyphenyl
15 isocyanate was reacted with 4-(4-(l-(7V-methoxy)iminoethyl)phenoxy aniline HC1 salt to
Method C 1 a to afford the urea.

Entry 27: 4-Chloro~A^methylpyridinecarboxamide was synthesized as described in Method
A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method
20 A2, Step 4 to give 4-(4-(2-(7V-methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-
methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate
according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with
4-(4-(2-(A r -methylcarb'ambyl)phenylthio)aniline according to Method Cla to afford the urea.

25 Entry 28: 5-(4-Aminophenoxy)-2-methylisoindoline-l,3-dione was synthesized according to
Method A9. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl
isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-l,3-dione according to
Method C 1 a to afford the urea.

30

Entry 29: 4-ChlorowV-methylpyridinecarboxamide was synthesized as described in Method
A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method

58

T

T

A2, Step 4 to give 3-(4-(2-(A r -methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-
methoxy aniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate
according to Method BL 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with
3-(4-(2-(A^-methylcarbamoyl)phenylthio)aniline according to Method Cla to afford the urea.

Entry 30: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according
to Method A2, Step 3b. The resulting 4-chloro-A r -isopropyl-2-pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(A r -
isopropylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was
converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(A r -
isopropylcarbamoyl)-4-pyridyloxy)aniline according to Method Cla to afford the urea.

Entry 31: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method
A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl
isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to
Method Cla to afford the urea. A r -(5-(Trifluoromethyl)-2-methoxyphenyl)-7V , -(4-(3-(5-
methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1,
and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the
amide according to Method D4, Step 2.

Entry 32: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method
A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl
isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to
Method Cla to afford the urea. A r -(5-(Trifluoromethyl)-2-methoxyphenyl)-A r '-(4-(3-(5-
methoxycarbonyipyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1,
and the corresponding acid was coupled with methylamine according to Method D4, Step 2
to afford the amide.

59

Entry 33: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method
A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-
methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl
isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to
Method Cla to afford the urea. AT-(5-(Trifluoromethyl)-2-methoxyphenyl)-A^ '-(4-(3-(5-
methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1 ,
and the corresponding acid was coupled with A^-dimethylethylenediamine according to
Method D4, Step 2 to afford the amide.

Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl
isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford ^-(5-
(trifluoromethyl)-2-methoxyphenyl)-A^-(3-carboxyphenyl) urea, which was coupled with 3-
aminopyridine according to Method Die.

Entry 35: 4-(3-Carboxyphenoxy) aniline was synthesized according to Method All. 5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl
isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5-
(trifluoromethyl)-2-methoxyphenyl)-JV '-(3-carboxyphenyl) urea, which was coupled with N-
(4-fluorophenyl)piperazine according to Method Die.

Entry 36: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-
(Trifluoromethyl)-2-methoxy aniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl
isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford iV-(5-
(trifluoromethyl)-2-methoxyphenyl)-iV -(3-carboxyphenyl) urea, which was coupled with 4-
fluoroaniline according to Method Die.

Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl

60

isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-{5-
(trifluoromethyl)-2-methoxyphenyl)-iV'-(3-carboxyphenyl) urea, which was coupled with 4-
(dimethylamino)aniline according to Method Die.

5

Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method AIL 5-
(Trifluoromethyl)-2-methoxy aniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl
isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford W-(5-
10 (trifluoromethyl)-2-methoxyphenyl)-iV -(3-carboxyphenyl) urea, which was coupled with 5-
amino-2-methoxypyridine according to Method Die.

Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method AIL 5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl
15 isocyanate according to Method BL 4-(3-Carboxyphenoxy)aniline was reacted with 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford A^-(5-
(trifluoromethyl)-2-methoxyphenyl)-A^ -(3-carboxyphenyl) urea, which was coupled with 4-
morpholinoaniline according to Method Die.

20 Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method AIL 5-
(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl
isocyanate according to Method BL 4-(3-Carboxyphenoxy)aniline was reacted with 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5-
(trifluoromethyl)-2-methoxyphenyl)-A r -(3-carboxyphenyl) urea, which was coupled with /V-

25 (2-pyridyl)piperazine according to Method Die.

Entry 41: 4-(3-(A r -Methylcarbamoyl)phenoxy)aniline was synthesized according to Method
A13. According to Method C3, 4-chloro-3-(trifluoromethyl)aniline was converted to the
isocyanate, then reacted with 4-(3-(A r -Methylcarbamoyl)phenoxy)aniline to afford the urea.

30

61

Entry 42: 4-(2wV-Methylcarbamyl-4-pyridyloxy)aniline was synthesized according to
Method A2. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-;V-
methylcarbamyl-4-pyridyloxy)aniline according to Method CI a to afford the urea.

5 Entry 43: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia
according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-
pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to
form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method CI a, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-carbamoyl-4-pyridyloxy)aniline to

10 afford the urea.

Entry 44: 4-Chloropyridine-2-carbonyl chloride HOI salt was reacted with ammonia
according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-
pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 to
15 form 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method CI a, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-carbamoyl-4-pyridyloxy)aniline to
afford the urea.

Entry 45: 4-Chloro-A r -methyl-2-pyridinecarboxamide, which was synthesized according to
20 Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to
form 3-(-2-(A^-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method CI a, 4-chloro-
3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(iV-methylcarbamoyl)-4-
pyridyloxy)aniline to afford the urea.

25 Entry 46: 5-(4-Aminophenoxy)isoindoline-l,3-dione was synthesized according to Method
A3. According to Method CI a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
with 5-(4-aminophenoxy)isoindoline-l,3-dione to afford the urea.

Entry 47: 4-(2-(A r -Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized
30 according to Method A5. According to Method Clc, 4-chloro-3-(trifluoromethyl)phenyI
isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-l,3-dione to afford the urea.

62

Entry 48: 4-(3-A^-Methylsulfamoyl)phenyloxy)aniline was synthesized according to Method
A15. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted
with 4-(3-A r -methylsulfamoyl)phenyloxy)aniline to afford the urea.

Entry 49: 4-(2-(A / '-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized
according to Method A6. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(2-(A r -methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to
afford the urea.

Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-
chloro- J /V-methyl-2-pyridinecarboxamide, which had been synthesized according to Method
A2, Step 3b, to give 3-(2-(A r -methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. According to
Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(A r -
methyIcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea.

Entry 51: 4-Chloropyridine-2-carbonyI chloride was reacted with ethylamine according to
Method A2, Step 3b. The resulting 4-chloro- J /V-ethyl-2-pyridinecarboxamide was reacted
with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(A^-ethylcarbamoyl)-4-
pyridy!oxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(2-(A^ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

Entry 52: According to Method A2, Step 4, 4-amino-2-chIorophenol was reacted with 4-
chloro-A r -methyl-2-pyridinecarboxamide, which had been synthesized according to Method
A2, Step 3b, to give 4-(2-(A r -methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. According to
Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(A r -
methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.

Entry 53: 4-(4-Methylthiophenoxy)-l -nitrobenzene was oxidized according to Method A19,
Step 1 to give 4-(4-methylsulfonylphenoxy)-l -nitrobenzene. The nitrobenzene was reduced
according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-l -aniline. According
to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-
methylsulfonylphenoxy)-! -aniline to afford the urea.

63

Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to
Method A15, Step 1 to afford /V-methyl-4-bromobenzenesulfonamide. Af-Methyl-4-
bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to
afford 4-(4-(A r -methylsulfamoyl)phenoxy)benzene. 4-(4-(/V-

5 Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(A r -methylsulfamoyl)phenoxy)-
1 -nitrobenzene according to Method A15, Step 3. 4-(4-(iV-Methylsulfamoyl)phenoxy)-l-
nitrobenzene was reduced to 4-(4-Af-methylsulfamoyl)phenyloxy)aniline according to
Method A15, Step 4. According to Method CI a, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(3-A^-methylsulfamoyl)phenyloxy)aniline to afford the urea.

10

Entry 55: 5-Hydroxy-2-methylpyridine was coupled with l-fluoro-4-nitrobenzene according
to Method A18, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenzene. The
methylpyridine was oxidized according to the carboxylic acid, then esterified according to
Method A18, Step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-l -nitrobenzene. The
15 nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2-
methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3-
(trifluoromethyl)phenyl isocyanate according to Method CI a to afford the urea.

Entry 56: 5-Hydroxy-2-methylpyridine was coupled with l-fluoro-4-nitrobenzene according
20 to Method A18, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-l -nitrobenzene. The
methylpyridine was oxidized according to the carboxylic acid, then esterified according to
Method A18, Step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-l -nitrobenzene. The
nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2-
methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3-
25 (trifluoromethyl)phenyl isocyanate according to Method Cla to give A r -(4-chloro-3-
(trifluoromethyl)phenyI)-A r '-(4-(2-(methoxycarbonyl)-5-pyridyloxy)phenyl) urea. The
methyl ester was reacted with methylamine according to Method D2 to afford 7V-(4-chloro-3-
(trifluoromethyl)phenyl)-A^^(4-(2-(A r -methylcarbamoyl)-5-pyridyloxy)phenyl) urea.

30 Entry 57: A^-(4-Chloro-3-(trifluoromethyl)phenyl-N -(4-aminophenyt) urea was prepared
according to Method Cld. iV-(4-Chioro-3-(trifluoromethyl)phenyl-iV-(4-aminophenyl) urea
was coupled with mcwo-methyl isophthalate according to Method Dla to afford the urea.

64

Entry 58: yV-(4-Chloro-3-(trifluoromethyl)phenyl-iV'-(4-aminophenyl) urea was prepared
according to Method Cld. A r .(4-Chloro-3-(trifluoromethyl)phenyl-A r -(4-aminophenyl) urea
was coupled with morto-methyl isophthalate according to Method Dla to afford A r -(4-chloro-
3Ktrifluoromethyl)phenyi-/V r '-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea.
According to Method D2, iV-(4-chloro-3-(trifluoromethyl)phenyl-A r '-(4-(3-
methoxycarbonylphenyl)carboxyaminophenyl) urea was reacted with methylamine to afford
the corresponding methyl amide.

Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according
to Method A2, Step 3b. The resulting 4-chloro-A^A r -dimethyl-2-pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(7V,A r -
dimethylcarbamoyl)-4-pyridyloxy)aniline. According to Method CI a, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(A^ J A r -dimethylcarbamoyl)-4-
pyridyloxy)aniline to afford the urea.

Entry 60: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to
Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was
reduced according to Method 13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was
converted to the 4-(4-(l-(AT-methoxy)iminoethyl) phenoxy aniline HC1 salt according to
Method A16. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was
reacted with 4-(4-acetylphenoxy)aniline to afford the urea.

Entry 61: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A13,
Step 2. 4-(3-Carboxyphenoxy)-l -nitrobenzene was - coupled with 4-(2-

aminoethyl)morpholine according to Method A13, Step 3 . to give 4-(3-(iV-(2-
morpholinyiethyl)carbamoyl)phenoxy)-l -nitrobenzene. According to Method A13 Step 4, 4-
(3-(A r -(2-morpholinylethyl)carbamoyl)phenoxy)-l -nitrobenzene was reduced to 4-(3-(A r -(2-
morpholinylethyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(iV-(2-
morpholinylethyl)carbamoyl)phenoxy)aniline to afford the urea.

65

Entry 62: 4-(3-Carboxyphenoxy)-l -nitrobenzene was synthesized according to Method A13,
Step 2. 4-(3-Carboxyphenoxy)-l -nitrobenzene was coupled with l-(2-aminoethyl)piperidine
according to Method A13, Step 3 to give 4-(3-(A^-(2-piperidylethyl)carbamoyl)phenoxy)-l-
nitrobenzene. According to Method A13 Step 4, 4-(3-(;V-(2-

piperidylethyl)carbamoyl)phenoxy)-l -nitrobenzene was reduced to 4-(3-(A r -(2-
piperidylethyl)carbamoyl)phenoxy)aniline. According to Method CI a, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(;V-(2-
piperidylethyl)carbamoyl)phenoxy)aniline to afford the urea.

Entry 63: 4-(3-Carboxyphenoxy)-l -nitrobenzene was synthesized according to Method A13,
Step 2. 4-(3-Carboxyphenoxy)-l -nitrobenzene was coupled with tetrahydrofurfuryl amine
according to Method A13, Step 3 to give 4-(3-(A r -
(tetrahydrofurylmethyl)carbamoyl)phenoxy)-l -nitrobenzene. According to Method A13 Step
4, 4-( 3 -(7V-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-l -nitrobenzene was reduced to 4-(3-
(yV-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline. According to Method CI a, 4-chloro-
3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-<7V-
(tetrahydrofurylmethyl)carbamoyl) phenoxy)aniline to afford the urea.

Entry 64: 4-(3-Carboxyphenoxy)-l -nitrobenzene was synthesized according to Method A13,
Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was coupled with 2-aminomethyM-
ethylpyrrolidine according to Method A13, Step 3 to give 4-(3-(A r -((l-
methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-l -nitrobenzene. According to Method A13
Step 4, 4-(3-(7V-(( 1 -methylpyrrolidinyl)methyl)carbamoyl)phenoxy)- 1 -nitrobenzene was
reduced to 4-(3-(A r -((l-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline. According to
Method CI a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(iV-((l-
methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline to afford the urea.

Entry 65: 4-Chloro-A r -methylpyridinecarboxamide was synthesized as described in Method
A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method
A2, Step 4 to give 4-(4-(2-(A^-methylcarbamoyl)phenylthio)aniline. According to Method
CI a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(7V r -
methylcarbamoyl)phenylthio)aniline to afford the urea.

66

Entry 66: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according
to Method A2, Step 3b. The resulting 4-chloro-iV-isopropyl-2-pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(vV-
isopropylcarbamoyl)-4-pyridyloxy)aniline. According to Method CI a, 4-chloro-3-
(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(vV-isopropylcarbamoyl)-4-
pyridyloxy)aniline to afford the urea.

Entry 67: A r -(4-Chloro-3-(trifluoromethyl)phenyl-A^ -(4-ethoxycarbonylphenyl) urea was
synthesized according to Method Cle. A r -(4-Chloro-3-(trifluoromethyl)phenyl-A r '-(4-
ethoxycarbonylphenyl) urea was saponified according to Method D3 to give 7V-(4-chloro-3-
(trifluoromethyl)phenyl-A r '-(4-carboxyphenyl) urea. A r -(4-Chloro-3-(trifluoromethyl)phenyl-
;V-(4-carboxyphenyl) urea was coupled with 3-methylcarbamoylaniline according to Method
D 1 b to give A r -(4-chloro-3 -(trifluoromethy Ophenyl-TV '-(4-(3 -

methylcarbamoylphenyl)carbamoylphenyl) urea.

Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline-l,3-dione was synthesized according to
Method A9. According to Method CI a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was
reacted with 5-(4-aminophenoxy)-2-methylisoindoline-l,3-dione to afford the urea.

Entry 69: 4-Chloro- J /V-methylpyridinecarboxamide was synthesized as described in Method
A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method
A2, Step 4 to give 3-(4-(2-(iv"-methylcarbamoyl)phenylthio)aniline. According to Method
CI a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(jV-
methylcarbamoyl)phenylthio)aniline to afford the urea.

Entry 70: 4-(2-(A r -(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized
according to Method A10. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(2-(A r -(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to
afford the urea.

67

Entry 71 : 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method
A14. 4-Chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. ^-(4-
ChloroO-(trifluoromethyl)phenyl)-A r, K4^3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea
was saponified according to Method D4, Step 1, and the corresponding acid was coupled with
4-(2-aminoethyl)morpholine to afford the amide.

Entry 72: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method
A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. iV-(5-
(Trifluoromethyl)-2-methoxyphenyl)^ urea
was saponified according to Method D4, Step 1, and the corresponding acid was coupled with
methylamine according to Method D4, Step 2 to afford the amide.

Entry 73: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method
A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. iV-(5-

(Trifluoromethyl)-2-methoxypheny0 urea
was saponified according to Method D4, Step 1, and the corresponding acid was coupled with
A^-dimethylethylenediamine according to Method D4, Step 2 to afford the amide.

Entry 74: 4-Chloropyridine-2-carbonyl ; chloride HC1 salt was reacted with 2-
hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-A r -(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-yV-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride,
followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(7V-(2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method Cla, 4-chloro-
3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(A r -(2-
triisopropylsilyloxy)ethylcarbamoyl) pyridyloxyaniline to afford A r -(4-chloro-3-
((trifluoromethyl)phenyl)-A^-(4-(4-(2-(A^-(2-triisopropylsilyloxy)
ethylcarbamoyl)pyridyloxyphenyl) urea.

68

Entry 75: 4-(3-Carboxyphenoxy)aniIine was synthesized according to Method All. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-
methoxycarbonyl)pyridyloxy)aniline according to Method Clf to afford the urea, which was
coupled with 3-aminopyridine according to Method Die.

5

Entry 76: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline
according to Method Clf to afford the urea, which was coupled with /V-(4-
acetyiphenyl)piperazine according to Method Die.

10

Entry 77: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Ail. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline
according to Method Clf to afford the urea, which was coupled with 4-fluoroaniline
according to Method Die.

15

Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline
according to Method Clf to afford the urea, which was coupled with 4-
(dimethylamino)aniline according to Method Die.

20

Entry 79: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline
according to Method Clf to afford the urea, which was coupled with N-
phenylethylenediamine according to Method Die.

25

Entry 80: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline
according to Method Clf to afford the urea, which was coupled with 2-methoxyethylamine
according to Method Die.

30

Entry 81: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline

69

according to Method Clf to afford the urea, which was coupled with 5-amino-2-
methoxypyridine according to Method Die.

Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline
according to Method Clf to afford the urea, which was coupled with 4-morpholinoaniline
according to Method Die.

Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-
Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline
according to Method Clf to afford the urea, which was coupled with iV-(2-pyridyl)piperazine
according to Method Die.

Entry 84: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with 2-
hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-jV-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-A r -(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride,
followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(A r -(2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method CI a, 4-chloro-
3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(AT-(2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline to give A^-(4-chloro-3-
((trifluoromethyl)phenyl)-^/-(4-(4-(2-(7V-(2-

triisopropylsilyloxy)ethylcarbamoyl)pyridyioxyphenyl) urea. The urea was deprotected
according to Method D5 to afford A r -(4-chloro-3-((trifluoromethyl)phenyl)-A r, -(4-(4-(2-(iV-(2-
hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea.

Entry 85: 4-(2-(A r -Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to
Method A2. 4-Bromo-3-(trifluoromethyl)aniline was converted to 4-bromo-3-
(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a, 4-
bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(A r -methylcarbamoyl)-4-
pyridyloxy)aniline to afford the urea.

70

Entry 86 : 4-(2-(A r -Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized
according to Method A6. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-
(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a, 4-
bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(7V-methylcarbamoyl)-4-
5 pyridyloxy)-2-chloroaniline to afford the urea.

Entry 87: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-
chloro-iV-methyl-2-pyridinecarboxamide, which had been synthesized according to Method
A2, Step 3b, to give 4-(2<A r -methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Bromo-3-
10 (trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate
according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(2-(A^-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to
afford the urea.

15 Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to
Method A2, Step 3b. The resulting 4-chloro-A r -ethyl-2-pyridinecarboxamide was reacted
with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(^-ethylcarbamoyl)-4-
pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-
(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-

20 bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(iV-ethylcarbamoyl)-4-
pyridyloxy)aniline to afford the urea.

Entry 89: 4-Chloro-A r -methyl-2-pyridinecarboxamide, which was synthesized according to
Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to
25 form 3-(-2-(A r -methylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline
was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method BL
According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-
(_2-(A^-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

30 Entry 90: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-
chloro-A^-methyl-2-pyridinecarboxamide, which had been synthesized according to Method
A2, Step 3b, to give 3-(2-(A^-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. 4-Bromo-3-

71

(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate
according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl
isocyanate was reacted with 3-(2-(A^mcthylcarbamoyl)-4-pyridyloxy)-4-methylaniline to
afford the urea.

5

Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according
to Method A2, Step 3b. The resulting 4-chloro-iV,A r -dimethyl-2-pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N~
dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was

10 converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl.
According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-
(2-(A r ,7V r -dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

Entry 92: 4-ChlorowV-methylpyridinecarboxamide was synthesized as described in Method
15 A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method
A2, Step 4 to give 4-(4-(2-(A r -methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-
(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate
according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl
isocyanate was reacted with 4-(4-(2-(A^-methylcarbamoyl)phenylthio)aniline to afford the
20 urea.

Entry 93: 4-Chloro-A r -methylpyridinecarboxamide was synthesized as described in Method
A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method
A2, Step 4 to give 3-(4-(2-(A r -methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-
25 (trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate
according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl
isocyanate was reacted with 3-(4-(2-(//-methylcarbamoyl)phenylthio)aniline to afford the
urea.

30 Entry 94: 4-(2-(^-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized
according to Method A10. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-
3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-

72

T

bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(A r -(2-Morpholin-4-
ylethyi)carbamoyl)pyridyloxy)aniline to afford the urea.

Entry 95: 4-(2-(A r -Methylcarbamoyl)-4-pyridyioxy)aniline was synthesized according to
Method A2. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to
Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-
methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to
Method CI a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-
(2-(7V-methylcarbamoyl)-4-pyridyIoxy)aniline to afford the urea.

Entry 96: 4-(2-(A r -Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized
according to Method A6. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized
according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into
4-chIoro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method Bl.
According to Method CI a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was
reacted with 4-(2-(A r -methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline afford the urea.

Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-
chloro-A^methyl-2-pyridinecarboxamide, which had been synthesized according to Method
A2, Step 3b, to give 4-(2-(A^methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Chloro-2-
methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-
methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-
(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a, 4-
chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(A r -
methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.

Entry 98: 4-Chloro-A r -methyl-2-pyridinecarboxamide, which was synthesized according to
Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to
form 3-(-2-(A r -methylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-
(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-
(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl
isocyanate according to Method Bl. According to Method CI a, 4-chloro-2-methoxy-5-

73

(trifiuoromethyl)phenyl isocyanate as was reacted with 3-(-2-(jV-methylcarbamoyl)-4-
pyridyloxy)aniline to afford the urea.

Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to
Method A2, Step 3b. The resulting 4-chloro-iV-ethyl-2-pyridinecarboxamide was reacted
with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(AT-ethylcarbamoyl)-4-
pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized
according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into
4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method Bl.
According to Method CI a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was
reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

Entry 100: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according
to Method A2, Step 3b. The resulting 4-chloro-M W-dimethyl-2-pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N.N-
dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline
was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline
was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to
Method Bl. According to Method CI a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl
isocyanate was reacted with 4<2-(Af,W-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the

urea.

Entry 101: 4-Chloro-AT-methyl-2-pyridinecarboxamide, which was synthesized according to
Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to
form 3-(-2-(iV-methylcarbamoyl)-4-pyridyloxy)aniline. 2-Amino-3-methoxynaphthalene was
synthesized as described Method Al. According to Method C3, 2-amino-3-
methoxynaphthalene was reacted with bis(trichloromethyl) carbonate followed by 3-(-2-(N-
methylcarbamoyl)-4-pyridyloxy)aniline to form the urea.

Entry 102: 4-(2-(iV-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to
Method A2. 5-rerr-Butyl-2-(2,5-dimethylpyrrolyl)aniline was synthesized according to

74

Method A4. 5-ferr-Butyl-2-(2,5-dimethylpyrrolyl)aniline was reacted with CDI followed by
4-(2-(A r -methylcarbamoyl)-4-pyridyloxy)aniline according to Method C2d to afford the urea.

Entry 103: 4-Chloro-A r -methyl-2-pyridinecarboxamide was synthesized according to Method
5 A2, Step 3b. 4-Chloro-A r -methyl-2-pyridinecarboxamide was reacted with 4-aminophenol
according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(A r -
methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2b, reaction of 3-amino-2-
methoxyquinoline with CDI followed by 4-(2-(A r -methylcarbamoyl)-4-pyridyloxy)aniline
afforded bis(4-(2-(A r -methylcarbamoyl)-4-pyridlyoxy)phenyl)urea.

10

Listed in the Tables below are compounds which have been synthesized according to
the Detailed Experimental Procedures given above:

15

Tables

20 The compounds listed in Tables 1-6 below were synthesized according to the general

methods shown above, and the more detailed exemplary procedures are in the entry listings
above and characterizations are indicated in the tables.

75

Table 1. 3-tert-Butylphenyl Ureas

H H

Entry

R

mp

(°C)

HPLC
(min.)

TLC

R f

TLC
Solvent
System

Mass
Spec.
[Source]

Synth.
Method

1

>-NH

0.22

50%
EtOAc
/ 50%
hexane

418

(M+H)+

(HPLC

ES-MS)

A13 C3

2

X = / Xl — 7 Me

0.58

50%
EtOAc
/ 50%
hexane

403

(M+H)+

(HPLC

ES-MS)

A13 C3

3

_Vnh

133-
135

0.68

100%
EtOAc

448

(M+H)+
(FAB)

A8 C2d

Table 2. 5-te/*-Butyl-2-methoxyphenyl Ureas

H H OMe

Entry

R

mp
(°C)

HPLC
(min.)

TLC
Rr

TLC
Solvent
System

Mass
Spec.
[Source]

Synth.
Method

4

O

y — nh

' -o-o Me

5.93

448

(M+H)+

(HPLC

ES-MS)

A13

Bl

Cla

5

o

V-NH

120-
122

0.67

100%
EtOAc

478

(M+H)+
(FAB)

A8
C2d

6

O

0.40

50%
EtOAc
/ 50%
hexane

460

(M+H)+

(HPLC

ES-MS)

A3
C2d

76

7

0.79

50%

446

Ai2

EtOAc

(M-rH)-

C2d

/ 50%

(HPLC

hexane

ES-MS)

Table 3.

5-(Trifluoromethyl)-2-methoxyphenyI Ureas

OMe

Entry

R

mp
(°C)

HPLC
(min.)

TLC

TT C

Solvent
System

Spec.
fSourcel

Synth.
Method

8

250
(dec)

460

(M+H)+

(r AB)

A13

C2a

9

^=N N ( Me

206-
208

0.54

10%
MeOH

/ y\J /o

CH2C1
2

446

(M+H)+
\ nrLL
ES-MS)

A3 step
2,

/\o bicp
4,
Bl.
Cla

10

0.33

50%
EtOAc
/ 50%
pet
ether

445

(M+H)+

(HPLC

ES-MS)

A13 C3

11

0.20

2%
Et3N/
98%
EtOAc

461

(M+H)+

(HPLC

ES-MS)

A2
C4

12

■hQ Vnh 2

0.27

1%

Et3N/

99%

EtOAc

447

(M+H)+

(HPLC

ES-MS)

A2
C4

13

o.

0.62

100%
EtOAc

461

(M+H)+
(FAB)

A2 C2a

14

o

J— NH 2

114-
117

0.40

1%
Et3N/
99%
EtOAc

447

(M+H)+
(FAB)

A2
C4

77

15

o

y-NH

/y vs n— u a) — OMe

\_/

232-
235

0.54

100% <
EtOAc (
(

190

M+H)+
FAB)

A8 C2d

16

O

Me )^-NH

_h. 0 ji, ' Me

210-
213

0.29

5%

MeOH {
/ 45% \
EtOAc
/ 50%
pet
ether

*75

[M+H)+

[HPLC

ES-MS)

A5

Bl Clc

17

o

CI V— NH

187-
188

0.17

50%
EtOAc
/ 50%
pet
ether

495

(M+H)+

(HPLC

ES-MS)

A6

Bl Cla

18

0.48

100%
EtOAc

475

(M+H)+

(HPLC

ES-MS)

A2 step
"4,

Bl Cla

19

o,

_Vnh

194-
196

031

5%

MeOH
/ 45%
EtOAc
I 50%
pet
ether

475

(M+H)+

(HPLC

ES-MS)

A2

Bl Cla

20

o

CI /-NH
^— ^ / C Me

214-
216

0.25

5%

MeOH
/ 45%
EtOAc
/ 50%
pet
ether

495

(M+H)+

(HPLC

ES-MS)

A2 Cla

21

208-
210

0J0

50%
EtOAc
/ 50%
hexane

481

(M+H)+

(HPLC

ES-MS)

A19C2a

22

o

— NH 2

188-
190

0.30

70%
EtOAc
/ 50%
hexane

447

(M+H)+

(HPLC

ES-MS)

A15,
step 4,
Cla

Z2

O

0.50

70%
EtOAc
/ 30%
hexane

472

(M+H)+
(FAB)

A3

Bl Cla

24

O Me

203-
205

0.13

100%
EtOAc

479

(M+H)+

(HPLC

ES-MS)

A2 Bl
Cla

78

25

0.09

75%
EtOAc
/ 25%
hexane

458

(M+H)+

(HPLC

ES-MS)

A12
C2d

26

MeO

169-
171

0.67

50%
EtOAc
/ 50%
pet
ether

474

(M+H)+

(HPLC

ES-MS)

A13
stepl,
A 13 step
4,

A16,

Bl

Cla

27

V-NH

218-
219

0.40

50%
EtOAc
/ 50%
pet
ether

477

(M+H)+

(HPLC

ES-MS)

A2 step
3b,

A2 step
4,
Bl,
Cla

28

^><K>f 0

V^NMe
O

212-
214

0.30

40%
EtOAc
/ 60%
hexane

A9

Bl Cla

29

/={ Me

0.33

50%
EtOAc
/ 50%
pet
ether

474

(M+H)+

(HPLC

ES-MS)

A2 step
3b,

A2 step
4,
Bl,
Cla

30

210-
211

A2
Bl
Cla

31

o

>-NH

210-
204

0.43

10%
MeOH

/

CH2C1
2

A14
Bl
Cla
D4

32

o

>-NH

247-
249

0.57

10%
MeOH

/

CH2C1
2

A14
Bl

PI a
L Id

D4

33

o

\ V~°~C V N-Me

v == / — N Me

217-
219

0.07

10%
MeOH

/

CH2C1
2

A14
Bl
Cla
D4

79

34

o

0.11

70%
EtOAc
/ 30%
hexane

All
Bl
Clf
Die

35

h

O

— N

0.38

70%
EtOAc
/ 30%
hexane

All
Bl
Clf
Die

36

F — ({ \-NH

0.77

70%
EtOAc
/ 30%
hexane

All
Bl
Clf
Die

37

N — \ y — NH
Me' X==/ _) =0

0.58

70%
EtOAc

/ 30%

All
Bl
Clf
Die

38

MeO— V y — NH

0.58

70%
EtOAc
/ 30%
hexane

All
Bl
Clf
Die

39

O N— \ V-NH

0.17

70%
EtOAc
/ 30%

HCA.O.I1C

All
Bl
Clf
Die

40

0.21

70%
EtOAc
/ 30%
hexane

All
Bl
Clf
Die

Table 4. 3-(Trifluoromethyl)-4-chlorophenyl Ureas

H H

80

Entry

R

mp

(°C)

HPLC

(min.)

TLC

TLC
Solvent
System

Mass
Spec.
[Source]

Synth.
Method

41

(}
V-NH

163-
165

0.08

50%
EtOAc/
50% pet
ether

464

(M+H)+

(HPLC

ES-MS)

A13
C3

42

V-NH

215

0.06

50%
EtOAc/
50% pet
ether

465

(M+H)+

(HPLC

ES-MS)

A2
Cla

43

o

V-NH 2

0.10

50%
EtOAc/
50% pet
ether

451

(M+H)+

(HPLC

ES-MS)

A2
Cla

44

0.25

30%
EtOAc/
70% pet
ether

451

(M+H)+

(HPLC

ES-MS)

A2
Cla

45

^n> Vnh

\=< /=< 'Me

0.31

30%
EtOAc/
70% pet
ether

465

(M+H)+

(HPLC

ES-MS)

A2
Cla

46

o

176-
179

0.23

40%
EtOAc/
60%
hexane

476

(M+H)+
(FAB)

A3
Cla

47

o

Me ^ — NH

^ v j ( Me

-o-o-o -

0.29

5%

MeOH/
45%
EtOAc/
50% pet
ether

478

(M+H)+

(HPLC

ES-MS)

A5
Clc

48

"S-NH

206-
209

A15
Cla

49

o

CI y-NH

147-
151

0.22

50%
EtOAc/
50% pet
ether

499

(M+H)+

(HPLC

ES-MS)

A6
Cla

50

— ^ V-Me ^ — NH
\=( /=( Me

0.54

100%
EtOAc

479

(M+H)+
(HPLC

ES-MS)

A2
Cla

81

51

o

ft — ^ /==( Et

187-
189

0.33

5%

MeOH/
45%
EtOAc/
50% pet
ether

479

(M-H)^

(HPLC

ES-MS)

A2
Cla

52

o,

CI >-NH

219

0.18

5%

MeOH/
45%
EtOAc/
50% pet
ether

499

(M+H)+

(HPLC

ES-MS)

A2
Cla

53

246-
248

0.30

50%
EtOAc/
50%
hexane

485

(M+H)+

(HPLC

ES-MS)

A 19, Cla

54

Q

NH

Me

200

a in

~7f\0/

IK) /o

EtOAc/

30%

hexane)

(M+H)+

(HPLC

ES-MS)

Cla

55

228-
230

0.30

30%
EtOAc/
70%
CH2C12

466

(M+H)+

(HPLC

ES-MS)

56

Me

238-
245

57

Vo

221-
222

0.75

80%
EtOAc/
20%
hexane

492

(M+H)+
(FAB)

Cld
Dla

58

V-NH

247

0.35

100%
EtOAc

Cld
Dla
D2

59

O v Me

198-
200

0.09

100%
EtOAc

479

(M+H)+

(HPLC

ES-MS)

AZ
Cla

60

MeO

158-
160

0.64

50%
EtOAc/
50% pet
ether

61

JVnh

^— o

195-
197

0.39

10%
MeOH/
CH2C1
2

A13
Cla

82

62

170-
172

0.52

10%
MeOH/
CH2C1
2

A13
Cla

63

168-
171

0.39

10%
MeOH/
CH2C1
2

A13
Cla

64

>-NH N-^

176-
177

0.35

10%
MeOH/
CH2C1
2

A13
Cla

65

Vnh

130-
133

487

(M+H)+

(HPLC

ES-MS)

A2
Bl
Cla

66

155

A2
Cla

67

y — nh

225-
229

0.23

100%
EtOAc

Cle

D3

Dlb

.68

V^NMe

234-
236

0.29

40%
EtOAc/
60%
hexane

A9
Cla

69

s -\>

0.48

50%
EtOAc/
50% pet
ether

481

(M+H)+

(HPLC

ES-MS)

70

-0- 0 A_^ N ( N -^

\— o

0.46

5%

MeOH/

95%

CH2C12

564

(M+H)+

(HPLC

ES-MS)

A10
Cla

83

71

O

^— o

199-
201

0.50

10%

MeOH/

CH2C1

7
L

A14
Cla
D4

72

V-NH
\=/ — N

235-
237

0.55

10%
MeOH/
CH2C1
2

A14
Cla
L>4

73

c>

\ /~° \v ^ N " Me

\=/ ^-N Me

200-
201

0.21

50%
MeOH/
CH2C1
2

A14
Cla
D4

74

— <f VO-( x ^ OSi(Pr-i) 3

145-
148

75

0.12

70%
EtOAc/
30%
hexane

527

(M+H)+

(HPLC

ES-MS)

All
Clf
Die

76

o

Q

O

— N

0.18

70%
EtOAc/
30%
hexane

All
Clf
Die

77

0.74

70%
EtOAc/
30%
hexane

All
Clf
Die

78

N— V >-NH
Me )=0

0.58

70%
EtOAc/
30%
hexane

All
Clf
Die

84

79

o

0.47

70%
EtOAc/
30%
hexane

569

(M+H)+

(HPLC

ES-MS)

All
Clf
Die

80

o

y— nh

0.18

70%
EtOAc/
30%
hexane

508

(M+H)+

(HPLC

ES-MS)

All
Clf
Die

81

0.58

70%
EtOAc/
30%
hexane

557

(M+H)+

(HPLC

ES-MS)

All
Clf
Die

82

(/ NH

0.37

70%
EtOAc/
30%
hexane

611

(M+H)+

(HPLC

ES-MS)

All
Clf
Die

83

o

^ — N

0.19

70%
EtOAc/
30%
hexane

All
Clf
Die

84

179-
183

A2
A17
Cla
D5

Table 5. 3-(Trifluoromethyl)-4-bromophenyl Ureas

H H

85

Entry

R

mp

(°9

HPLC
(min.)

TLC

K f

TLC
Solvent
System

Mass
Spec.
[Source]

Synth.
Method

85

Vnh

186-

187

0.13

50%
EtOAc/
50% pet
ether

509

;m+h)+

^HPLC ES-
MS)

A2
Bl

Cla

86

o

ci Vnh

150-
152

0.31

50%
EtOAc/
50% pet
ether

545

(M+H)+
(HPLC ES-
MS)

A6
Bl
Cla

87

o

CI V-NH

217-
219

0.16

50%
EtOAc/
50% pet
ether

545

(M+H)+
(HPLC ES-
MS)

A2
Bl
Cla

88

o.

_Vnh

183-
184

0.31

50%
EtOAc/
50% pet
ether

525

(M+H)+
(HPLC ES-
MS)

A2
Bl
Cla

89

0.21

50%
EtOAc/
50% pet
ether

511

(M+H)+
(HPLC ES-
MS)

A2
Bl
Cla

90

<f V-Me V-NH

\=<( /=\ Me

°-\J i

0.28

50%
EtOAc/
50% pet
ether

525

(M+H)+
(HPLC ES-
MS)

A2
Bl
Cla

Q 1
y 1

O Me

214-
216

0.28

50%
EtOAc/
50% pet
ether

522

(M+H)+
(HPLC ES-
MS)

A2
Bl
Cla

92

O

V-NH

0.47

50%
EtOAc/
50% pet
ether

527

(M+H)+
(HPLC ES-
MS)

A 2 step
3b,

A2 step
4,
Bl,
Cla

93

0.46

50%
EtOAc/
50% pet
ether

527

(M+H)+
(HPLC ES-
MS)

A2 step .
3b,

A2 step

4,

Bl,

Cla

86

Table 6. 5-(Trifluoromethyl)-4-chloro-2-methoxyphenyl Ureas

TLC

Mass

Entry

XV

mp

\ C )

HPLC
(min.)

TLC

Solvent
System

Spec.
[Source]

Synth.
Method

95

-NH

140-
144

0.29

5%

MeOH/

495

(M+H)+

A2
A7

-o°-

Me

45%
EtOAc/
50% pet
ether

(HPLC
ES-MS)

Bl
Cla

96

244-

0.39

5%

529

A6

-NH

245

MeOH/

(M+H)+

A7

Me

4j /o

EtOAc/
50% pet
ether

ES-MS)

Q t
t> I

Cla

97

220-

0.25

5%

529

A2

CI

-NH

221

MeOH/

(M+H)+

A7

■A

Me

45%
EtOAc/
50% pet
ether

(HPLC
ES-MS)

Bl
Cla

98

-Q

c-

0.27

5%

495

A2

/ — NH

MeOH/

(M+H)+

A7

o—

o

Me

45%
EtOAc/
50% pet
ether

(HPLC
ES-MS)

Bl

Cla

99

-NH

180-
181

0.52

5%

MeOH/

509

(M+H)+

A2
A7

45%
EtOAc/
50% pet
ether

(HPLC
ES-MS)

Bl
Cla

100

-0°-

-NH
Pr-i

162-
165

A2
A7
Bl
Cla

Table 7.

Additional Ureas

Entry

R

mp
(°C)

HPLC
(min.)

TLC

TLC
Solvent
System

Mass
Spec.
[Sourcel

Synth.
Method

101

\i N A N Xj IJ Me

I , . H H
OMe

162-
165

Al
A2
C3

102

L H H

0.10

50%
EtOAc/
50%
hexane

442

(M+H)+

(HPLC

ES-MS)

A2
A4
C2d

103

o

x

HN NH

0 0

o o

NH-Me Me— NH

125-
130

0.24

40%
EtOAc/
60%
hexane

512

(M+H)+
(FAB)

A2
C2b

5

The preceding examples can be repeated with similar success by substituting the generically
or specifically described reactants and/or operating conditions of this invention for those used
in the preceding examples.

10 From the foregoing description, one skilled in the art can easily ascertain the essential
characteristics of this invention and, without departing from the spirit and scope thereof, can
make various changes and modifications of the invention to adapt it to various usages and
conditions.

88

WHAT IS CLAIMED IS:

1 . A compound of Formula I:

A - D - B (I)
5 or a pharmaceutic ally acceptable salt thereof, wherein
D is -NH-C(0)-NH-,

A is a substituted moiety of up to 40 carbon atoms of the formula: -L~(M-L l ) q ,
where L is a 5 or 6 membered cyclic structure bound directly to D, L 1 comprises a
substituted cyclic moiety having at least 5 members, M is a bridging group having at least
10 one atom, q is an integer of from 1-3; and each cyclic structure of L and L 1 .contains 0-4
members of the group consisting of nitrogen, oxygen and sulfur, and

B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to
30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing
0-4 members of the group consisting of nitrogen, oxygen and sulfur,

15 wherein L 1 is substituted by at least one substituent selected from the group consisting

of-S0 2 R x , -C(0)R x and -C(NR y ) R z ,

R y is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally
containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per
halo,

20 R z is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally

containing heteroatoms selected from N, S and O and optionally substituted by halogen,
hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain
heteroatoms selected from N, S and O and are optionally substituted by halogen;

R x is R z or NR a Rb where R a and Rb are

25 a) independently hydrogen,

a carbon based moiety of up to 30 carbon atoms optionally containing
heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and

89

carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms
selected from N, S and O and are optionally substituted by halogen, or

-OSi(Rf)3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon
atoms optionally containing heteroatoms selected from N, S and O and optionally substituted
5 by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which
optionally contain heteroatoms selected from N, S and O and are optionally substituted by
halogen; or

b) R a and R b together form a 5-7 member heterocyclic structure of 1-3
heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of

10 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based
substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N,
S and O and are optionally substituted by halogen; or

c) one of R a or Rb is -C(O)-, a C1-C5 divalent alkylene group or a substituted Ci-
C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5

15 members, wherein the substituents of the substituted C1-C5 divalent alkylene group are
selected from the group consisting of halogen, hydroxy, and carbon based substituents of up
to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are
optionally substituted by halogen;

where B is substituted, L is substituted or L 1 is additionally substituted, the
20 substituents are selected from the group "consisting of halogen, up to per-halo, and Wn, where
n is 0-3;

wherein each W is independently selected from the group consisting of -CN, -C0 2 R 7 ,
-C(0)NR 7 R 7 , -C(0)-R 7 , -N0 2 , -OR 7 , -SR 7 , -NR 7 R 7 , -NR 7 C(0)OR 7 , -NR 7 C(0)R 7 , -Q-Ar, and
carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected
25 from N, S and O and optionally substituted by one or more substituents independently
selected from the group consisting of -CN, -C0 2 R 7 , -C(0)R 7 , -C(0)NR 7 R 7 , -OR 7 , -SR 7 , -
NR 7 R 7 , -N0 2 , -NR 7 C(0)R 7 , -NR 7 C(0)OR 7 and halogen up to per-halo; with each R 7
independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally
containing heteroatoms selected from N, S and O and optionally substituted by halogen,

90

wherein Q is -O-, -S-, -N(R 7 )-, -(CH 2 ) m -, -C(0)-, -CH(OH)-, -(CH 2 ) m O-, -(CH 2 ) m S-,
-(CH 2 ) m N(R 7 )-, -0(CH 2 ) m - CHX a -, -CXV, -S-(CH 2 ) m - and -N(R 7 )(CH 2 ) m -, where m- 1-3,
and X a is halogen; and

Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the
5 group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen,
up to per-halo, and optionally substituted by Z n i, wherein nl is 0 to 3 and each Z is
independently selected from the group consisting of -CN, -C0 2 R 7 , -C(0)R 7 , -C(0)NR 7 R 7 , -
N0 2 , -OR 7 , - SR 7 -NR 7 R 7 , -NR 7 C(0)OR 7 , -NR 7 C(0)R 7 , and a carbon based moiety of up to
24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally
10 substituted by one or more substituents selected from the group consisting of -CN, -C0 2 R 7 , -
COR 7 , -C(0)NR 7 R 7 , -OR 7 , -SR 7 , -N0 2 , -NR 7 R 7 , -NR 7 C(0)R 7 , and -NR 7 C(0)OR 7 , with R 7 as
defined above.

2. A compound as in claim 1 wherein:

15 R y is hydrogen, Cmo alkyl, Clio alkoxy, C3.10 cycloalkyl having 0-3 heteroatoms, C 2 .

10 alkenyl, C1-10 alkenoyl, C6-12 aryl, C3.L2 hetaryl having 1-3 heteroatoms selected from N, S
and O, C7-24 aralkyl, C7-24 alkaryl, substituted Cmo alkyl, substituted Cmo alkoxy, substituted
C3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and O, substituted Ce -Cu aryl,
substituted C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, substituted Cv- 2 4

20 alkaryl or substituted C7-Q4 aralkyl, where R y is a substituted group, it is substituted by
halogen up to per halo*

R z is hydrogen, Cmo alkyl, Cmo alkoxy, C3-10 cycloalkyl having 0-3 heteroatom, C 2 .10
alkenyl, Cmo alkenoyl, Ce-12 aryl, C3 -C12 hetaryl having 1-3 heteroatoms selected from, S, N

25 and O, C7-24 alkaryl , C7- 2 4 aralkyl, substituted Cmo alkyl, substituted Cmo alkoxy, substituted
C6-C14 aryl, substituted C3 -C10 cycloalkyl having 0-3 heteroatoms selected from S, N and O,
substituted C3.12 hetaryl having 1-3 heteroatoms selected from S, N and O, substituted C7- 2 4
alkaryl or substituted C7-C24 aralkyl where R z is a substituted group, it is substituted by
halogen up to per halo, hydroxy, Cmo alkyl, C3-i2 cycloalkyl having 0-3 heteroatoms selected

30 from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, Cmo

91

alkoxy, C ft . l2 aryl, Ci- 6 halo substituted alkyl up to per halo alkyl, C 6 -Ci2 halo substituted ary]
up to per halo aryl, C3-C12 halo substituted cycloalkyl up to per halo cycloalkyl having 0-3
heteroatoms selected from N, S and O, halo substituted C3-C 12 hetaryl up to per halo hetaryl
having 1-3 heteroatoms selected from O, N and S, halo substituted C 7 -C 24 aralkyl up to per
5 halo aralkyl, halo substituted C 7 -C 24 alkaryl up to per halo alkaryl, and -C(0)R g ,

R a and R b are,

a) independently hydrogen,

a carbon based moiety selected from te group consisting of Ci -do alkyl, C, -
10 do alkoxy, d-10 cycloalkyl, C2-10 alkenyl, d-10 alkenoyl, C 6 -i 2 aryl, C3-12 hetaryl having 1-3
heteroatoms selected from O, N and S, C3-12 cycloalkyl having 0-3 heteroatoms selected from
N, S and O, C7-24 aralkyl, C 7 -C 2 4 alkaryl, substituted C M0 alkyl, substituted d-io alkoxy,
substituted C3-10 cycloalkyl, having 0-3 heteroatoms selected from N, S and O, substituted C 6 -
12 aryl, substituted C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, substituted
15 C 7 ,24 aralkyl, substituted C7-24 alkaryl, where R a and R b are a substituted group, they are
substituted by halogen up to per halo, hydroxy, d-10 alkyl, d-12 cycloalkyl having 0-3
heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N,
S and O, C M0 alkoxy, C 6 -i2 aryl, d-6 halo substituted alkyl up to per halo alkyl, C 6 -C !2 halo
substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl having 0-3 heteroatoms
20 selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per
halo heteraryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C 7 -C 24
alkaryl up to per halo alkaryl, and -C(0)R g ; or

-OSi(R f ) 3 where R f is hydrogen, Clio alkyl, C M0 alkoxy, C3-C10 cycloalkyl
having 0-3 heteroatoms selected from O, S and N, C 6 -i2 aryl, C3-C12 hetaryl having 1-3

25 heteroatoms selected from O, S and N, C7-24 aralkyl, substituted C M0 alkyl, substituted C r
C10 alkoxy, substituted C 3 -Ci 2 cycloalkyl having 0-3 heteroatoms selected from O, S and N,
substituted C3-C12 heteraryl having 1-3 heteroatoms selected from O, S, and N, substituted
C 6 -i2 aryl, and substituted C 7 _ 2 4 alkaryl, where R f is a substituted group it is substituted
halogen up to per halo, hydroxy, d-10 alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected

30 from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C M0
alkoxy, C 6 . 12 aryl, C 7 -C 24 alkaryl, C 7 -C 2 4 aralkyl, Ci_ 6 halo substituted alkyl up to per halo

T

T

alkyl, C 6 -C t 2 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl
having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted
C3-C12 hetaryl up to per halo heteraryl, halo substituted C7-C24 aralkyl up to per halo aralkyl,
halo substituted C7-C24 alkaryl up to per halo alkaryl, and -C(0)R g ,

5 or

b) R a and Rb together form a 5-7 member heterocyclic structure of 1-3
heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of
1-3 heteroatoms selected from N, S and O with substituents selected from the group
consisting of halogen up to per halo, hydroxy, Ci-io alkyl, C3-12 cycloalkyl having 0-3

10 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N,
S and O, Q.io alkoxy, C 6 -i2 aryl, C 7 -C 2 4 alkaryl, C 7 -C 24 aralkyl, halo substituted Ci. 6 alkyl
up to per halo alkyl, halo substituted C 6 -Ci2 aryl up to per halo aryl, halo substituted C 3 -C 12
cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo
substituted C3-C12 hetaryl up to per halo heteraryl, halo substituted C7-C24 aralkyl up to per

15 halo aralkyl, halo substituted C 7 -C 24 alkaryl up to per halo alkaryl, and -C(0)R g ,

or

c) one of R a or R b is -C(O)-, a C1-C5 divalent alkylene group or a substituted C|-
Cs divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5

20 members,

wherein the substituents of the substituted Q-C5 divalent alkylene group are selected from
the group consisting of halogen, hydroxy, C M o alkyl, C3-12 cycloalkyl having 0-3 heteroatoms
selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, Ci_
10 alkoxy, Q-12 aryl, C 7 -C 2 4 alkaryl, C 7 -C24 aralkyl, Ci_ 6 halo substituted alkyl up to per halo
25 alkyl, C 6 -Ci 2 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl
having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted
C3-Q2 hetaryl up to per halo heteraryl, halo substituted C 7 -C 24 aralkyl up to per halo aralkyl,
halo substituted C7-C24 alkaryl up to per halo alkaryl, and -C(0)R g ,

where R g is C M0 alkyl; -CN, -C0 2 Rd, -OR* -SR<j, -N0 2 , -C(O) Re, -NRdRe, -
30 NRd C(0)ORe and -NRd C(0)Re, and R<i and are independently selected from the group

93

consisting of hydrogen, Cmo, alkyl, Cmo alkoxy, C3-10 cycloalkyl having 0-3 heteroatoms
selected from O, N and S, C 6 -i2 aryl, C3- C12 hetaryl with 1-3 heteroatoms selected from O, N
and S and C 7 -C24 aralkyl, C7 -C24 alkaryl, up to per halo substituted C1-C10 alkyl, up to per
halo substituted C 3 -C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, up to
5 per halo substituted C6 -Cu aryl, up to per halo substituted C3 -C12 hetaryl having 1-3
heteroatoms selected from O, N, and S, halo substituted C7-C24 alkaryl up to per halo alkaryl,
and up to per halo substituted C7-C24 aralkyl,

W is independently selected from the group consisting of -CN, -CO2R 7 , -C(0)NR 7 R 7 ,
10 -C(0)-R 7 , -N0 2 , -OR 7 , -SR 7 , -NR 7 R 7 , -NR 7 C(0)OR 7 , -NR 7 C(0)R 7 , C1-C10 alkyl, d-do
alkoxy, C2-C10 alkenyl, C1-C10 alkenoyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected
from O, S and N, Ca-Cu aryl, C7-C24 alkaryl, C7 -C24 aralkyl, C3-C12 heteroaryl having 1-3
heteroatoms selected from O, N and S, C4-C23 alkheteroaryl having 1-3 heteroatoms selected
from O, N and S, substituted Ci-C l0 alkyl, substituted C1-C10 alkoxy, substituted C2-C10
15 alkenyl, substituted C1-C10 alkenoyl, substituted C3-C10 cycloalkyl having 0-3 heteroatoms
selected from O, N and S, substituted C6-C12 aryl, substituted C3-C12 hetaryl having 1-3
heteroatoms selected from O, N and S, substituted C7-C24 aralkyl, substituted C7-C24 alkaryl,
substituted C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, and -Q-
Ar;

20

R 7 is independently selected from H, Ct-Cio alkyl, C1-C10 alkoxy, C2-C10 alkenyl, d-
C10 alkenoyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C6-C14
aryl, C3-C13 hetaryl having 1-3 heteroatoms selected from O, N and S, C7-C14 alkaryl, C 7 -C24
aralkyl, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, up to per-
25 halosubstituted C1-C10 alkyl, up to per-halosubstituted C3-C10 cycloalkyl having 0-3
heteroatoms selected from O, N and S, up to per-halosubstituted C6-C14 aryl, up to per-
halosubstituted C3-C13 hetaryl having 1-3 heteroatoms selected from O, N and S, up to per-

halosubstituted C7-C24 aralkyl, up to per-halosubstituted C7-C24 alkaryl, and up to per-
halosubstituted C4-C23 alkheteroaryl; and

30

94

1

each Z is independently selected from the group consisting of -CN, -CO2R 7 , -C(0)R 7 ,
-C(0)NR 7 R 7 , -N0 2 , -OR 7 , - SR 7 -NR 7 R 7 , -NR 7 C(0)0R 7 , -NR 7 C(0)R 7 , C r C 10 alkyl, C1-C10
alkoxy, C 2 -C\ 0 alkenyl, C1-C10 alkenoyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected
from O, N and S, C6-C14 aryl, C3-C13 hetaryl having 1-3 heteroatoms selected from O, N and
5 S, C7-C24 alkaryl, C 7 -C 24 aralkyl, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from
O, N and S, substituted C1-C10 alkyl, substituted C1-C10 alkoxy, substituted C 2 -Ci 0 alkenyl,
substituted Ci-Cio alkenoyl, substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected
from O, N and S, substituted C 6 -C 12 aryl, substituted C7-C24 alkaryl, substituted C 7 -C 2 4
aralkyl and substituted C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N
10 and S; wherein if Z is a substituted group, the one or more substituents are selected from the
group consisting of -CN, -C0 2 R 7 , -COR 7 , -C(0)NR 7 R 7 , -OR 7 , -SR 7 , -N0 2 , -NR 7 R 7 ,
-NR 7 C(0)R 7 , and -NR 7 C(0)0R 7 .

3. A compound as in claim 1 wherein M is one or more bridging groups selected
15 from the group consisting of -O-, -S-, -N(R 7 )-, -(CH 2 ) m -, -C(O)-, -CH(OH)-, -(CH 2 ) m O-, -

(CH 2 ) m S-, -(CH 2 ) m N(R 7 )-, -0(CH 2 ) m - CHX\ -CX a 2 -> -S-(CH 2 ) m - and -N(R 7 )(CH 2 ) m -, where
m= 1-3, X a is halogen and R 7 is as defined in claim 1.

4. A compound as in claim 1 wherein the cyclic structures of B and L bound
directly to D are not substituted in the ortho position by-OH.

20 5. A compound as in claim 1 wherein the cyclic structures of B and L bound

directly to D are not substituted in the ortho position by a moiety having an ionizable
hydrogen and a pKa of 10 or less.

6. A compound of claim 1 wherein B of Formula I is a substituted or
unsubstituted six member aryl moiety or six member hetaryl moiety, said hetaryl moiety

25 having 1 to 4 members selected from the group of hetaryl atoms consisting of nitrogen,
oxygen and sulfur with the balance of the hetaryl moiety being carbon.

7. A compound of claim 1 wherein B of Formula I is an unsubstituted phenyl
group, an unsubstituted pyridyl group, an unsubstituted pyrimidinyl, a phenyl group
substituted by a substituent selected from the group consisting of halogen and Wn wherein W

30 and n are as defined in claim 1, a pyrimidinyl group substituted by a substituent selected from

95

the group constituting of halogen and Wn, whereas W and n are as defined in Claim 1, or a
substituted pyridyl group substituted by a substituent selected from the group consisting of
halogen and Wn wherein W and n are as defined in claim 1 .

8. A compound of claim 6 wherein B of Formula I is a substituted phenyl group,
5 a substituted pyrimidinyl group, or substituted pyrridyl group substituted 1 to 3 times by 1 or

more substituents selected from the group consisting of -CN, halogen, Ci-Cio alkyl, Ci-Cio
alkoxy, -OH, up to per halo substituted Ci-Cio alkyl, up to per halo substituted Ci-Qo alkoxy
or phenyl substituted by halogen up to per halo.

9. A compound of claim 1, wherein L, the six member cyclic structure bound
10 directly to D, is a substituted or unsubstituted 6 member aryl moiety or a substituted or

unsubstituted 6 member hetaryl moiety, wherein said hetaryl moiety has 1 to 4 members
selected from the group of heteroatoms consisting of nitrogen, oxygen and sulfur with the
balance of said hetaryl moiety being carbon, wherein the one or more substituents are
selected from the group consisting of halogen and Wn wherein W and n are as defined in
15 claim 1.

10. A compound of claim 8, wherein L, the 6 member cyclic structure bound
directly to D, is a substituted phenyl, unsubstituted phenyl, substituted pyrimidinyl,
unsubstituted pyrimidinyl, substituted pyridyl or unsubstituted pyridyl group.

11. A compound of claim 1, wherein said substituted cyclic moiety L 1 comprises a
20 5 to 6 membered aryl moiety or hetaryl moiety, wherein said heteraryl moiety comprises 1 to

4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulfur.

12. A compound of claim 1, wherein said substituted cyclic moiety L 1 is phenyl,
pyridinyl or pyrimidinyl.

13. A compound of claim 3, wherein said substituted cyclic moiety L l is phenyl,
25 pyridinyl or pyrimidinyl.

14. A compound of claim 6, wherein said substituted cyclic moiety L 1 is phenyl,
pyridinyl or pyrimidinyl.

15. A compound of claim 8, wherein said substituted cyclic moiety L 1 is phenyl,
pyridinyl or pyrimidinyl.

96

16. A compound of claim 9, wherein said substituted cyclic moiety L l is phenyl,
pyridinyl or pyrimidinyl.

17. A compound of claim 10, wherein said substituted cyclic moiety L 1 is phenyl,
pyridinyl or pyrimidinyl.

5 18. A compound of claim 14, wherein M is one or more bridging groups selected

from the group consisting of ^O-, -S-, -N(R 7 )-, -(CH 2 ) m -, -C(O)-, -CH(OH)-, -(CH 2 ) m O-, -
(CH 2 ) m S-, -(CH 2 ) m N(R 7 )-, -0(CH 2 ) m - CHX\ -CXV, -S-(CH 2 ) m - and ^N(R 7 )(CH 2 ) m -, where
m= 1-3, X a is halogen and R 7 is hydrogen or a carbon based moiety of up to 24 carbon atoms,
optionally containing heteroatoms selected from N, S and O and optionally substituted by

10 halogen up to per halo.

19. A compound of claim 15, wherein M is one or more bridging groups selected
from the group consisting of -O-, -S-, -N(R 7 )-, -(CH 2 ) m -, -C(O)-, -CH(OH)-, -(CH 2 ) m O-, -
(CH 2 ) m S-, -(CH 2 ) m N(R 7 )-, -0(CH 2 ) m - CHX\ -CXV, -S-(CH 2 ) m - and -N(R 7 )(CH 2 ) m -, where
m = i_3 ? x a is halogen and R 7 is hydrogen or a carbon based moiety of up to 24 carbon atoms,

15 optionally containing heteroatoms selected from N, S and O and optionally substituted by
halogen up to per halo.

20. A compound of claim 16, wherein M is one or more bridging groups selected
from the group consisting of -O-, -S-, -N(R 7 )-, -(CH 2 ) m -, -C(O)-, -CH(OH)-, -(CH 2 ) m O-, -
(CH 2 ) m S-, -(CH 2 ) m N(R 7 )-, -0(CH 2 ) m - CHX a -, -CXV, -S-(CH 2 ) m - and -N(R 7 )(CH 2 ) m -, where

20 m= 1-3, X a is halogen and R 7 is hydrogen or a carbon based moiety of up to 24 carbon atoms,
optionally containing heteroatoms selected from N, S and O and optionally substituted by
halogen up to per halo.

21 . A compound of claim 17, wherein M is one or more bridging groups selected
from the group consisting of -O-, -S-, -N(R 7 )-, -(CH 2 ) m -, -C(O)-, -CH(OH)-, -(CH 2 ) m O-, -

25 (CH 2 ) m S-, -(CH 2 ) m N(R 7 )-, -0(CH 2 ) m - CHX a -, -CX a 2 -, -S-(CH 2 ) m - and .N(R 7 )(CH 2 ) m -, where
m = i-3, X a is halogen and R 7 is hydrogen or a carbon based moiety of up to 24 carbon atoms,
optionally containing heteroatoms selected from N, S and O and optionally substituted by
halogen up to per halo.

22. A compound of claim 1 wherein L 1 is additionally substituted 1 to 3 times by
30 one or more substituents selected from the group consisting of CrQo alkyl, up to per halo

97

substituted C1-C10 alkyl, -CN, -OH, halogen, Ci-C i0 alkoxy and up to per halo substituted C r
Cio alkoxy.

23. A compound of claim 13 wherein L 1 is additionally substituted 1 to 3 times by
one or more substituents selected from the group consisting of Ci-Cio alkyl, up to per halo

5 substituted Ci-Cio alkyl, -CN, -OH, halogen, Ci-Cio alkoxy and up to per halo substituted Cr
do alkoxy.

24. A compound of claim 18 wherein L 1 is additionally substituted 1 to 3 times by
one or more substituents selected from the group consisting of Cj-Cio alkyl, up to per halo
substituted Cj-Cio alkyl, -CN, -OH, halogen, Ci-Cio alkoxy and up to per halo substituted C\-

10 Cio alkoxy.

25. A compound of claim 19 wherein L 1 is additionally substituted 1 to 3 times by
one or more substituents selected from the group consisting of Ci-Cjo alkyl, up to per halo
substituted Cj-Cio alkyl, -CN, -OH, halogen, Ci-Cio alkoxy and up to per halo substituted Cr
Cio alkoxy.

15 26. A compound of claim 20 wherein L 1 is additionally substituted 1 to 3 times by

one or more substituents selected from the group consisting of Ci-Cio alkyl, up to per halo
substituted Ci-Cjo alkyl, -CN, -OH, halogen, Ci-Cio alkoxy and up to per halo substituted d-
C io alkoxy.

27. A compound of claim 21 wherein L 1 is additionally substituted 1 to 3 times by
20 one or more substituents selected from the group consisting of Ci-Cio alkyl, up to per halo

substituted Ci-Cio alkyl, -CN, -OH, halogen, Ci-Cio alkoxy and up to per halo substituted Ci-
Cio alkoxy.

28. A compound of claim 1 wherein L l is substituted by -C(0)R x .

29. A compound of claim 1 wherein L 1 is substituted by -SO2RX -

25 .30. A compound of claim 1 wherein L 1 is substituted only by -C(0)R x .

31. A compound of claim 1 wherein L 1 is substituted only by -SO2RX ■

32. A compound of claim 1 wherein L 1 is substituted by -C(0)R x or -S02R X ,
wherein R x is NR a Rb-

98

33. A compound of claim 13 wherein L l is substituted by -C(0)R x or -SO : R x ,
wherein R x is NR a R b , and R a and R b are

a) independently hydrogen,

a carbon based moiety of up to 30 carbon atoms optionally containing
5 heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and
carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms
selected from N, S and O and are optionally substituted by halogen, or

-OSi(Rf)3 where R f is hydrogen or a carbon based moiety of up to 24 carbon
atoms optionally containing heteroatoms selected from N, S and O and optionally substituted
10 by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which
optionally contain heteroatoms selected from N, S and O and are optionally substituted by
halogen; or

b) R a and R b together form a 5-7 member heterocyclic structure of 1-3
heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of

15 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based
substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N,
S and O and are optionally substituted by halogen; or

c) one of R a or R b is -C(O)-, a Ct-C 5 divalent alkylene group or a substituted C r
C 5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5

20 members, wherein the substituents of the substituted C t -C 5 divalent alkylene group are
selected from the group consisting of halogen, hydroxy, and carbon based substituents of up
to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are
optionally substituted by halogen.

34. A compound of claim 18 wherein L l is substituted by -C(0)R x or -S0 2 Rx,
25 wherein R x is NR a R b and R a and R b are independently hydrogen or a carbon based moiety

of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and

optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon
atoms, which optionally contain heteroatoms selected from N, S and O and are optionally
substituted by halogen.

99

35. A compound of claim 19 wherein L 1 is substituted by -C(0)R X) wherein R x is
NR a R b and R a and R b are independently hydrogen or a carbon based moiety of up to 30
carbon atoms optionally containing heteroatoms selected from N, S and O and optionally
substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms,

5 which optionally contain heteroatoms selected from N, S and O and are optionally
substituted by halogen.

36. A compound of claim 20 wherein L l is substituted by -C(0)R x or -SC^Rx,
wherein R x is NR a Rb and R a and R b are independently hydrogen or a carbon based moiety
of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and

10 optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon
atoms, which optionally contain heteroatoms selected from N, S and O and are optionally
substituted by halogen.

37. A compound of claim 21 wherein L 1 is substituted by -C(0)R x or -SC^R*,
wherein R x is NR a Rb and R a and Rb are independently hydrogen or a carbon based moiety

15 of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and
optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon
atoms, which optionally contain heteroatoms selected from N, S and O and are optionally
substituted by halogen.

20 38. A compound of Formula I:

A - D - B (I)
or a pharmaceutical^ acceptable salt thereof, wherein
D is -NH-C(0)-NH-,

A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L ] ) q ,
25 where L is a 6 membered aryl moiety or a 6 membered hetaryl moiety bound directly to D,
L 1 comprises a substituted cyclic moiety having at least 5 members, M is a bridging group
having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L 1
contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and

100

B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to
30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing

0- 4 members of the group consisting of nitrogen, oxygen and sulfur,

wherein L 1 is substituted by at least one substituent selected from the group consisting
5 of -S0 2 R x , -C(0)R x and -C(NR y ) R z ,

R y is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally
containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per
halo,

R z is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally
10 containing heteroatoms selected from N, S and O and optionally substituted by halogen,
hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain
heteroatoms selected from N, S and O and are optionally substituted by halogen;

R x is R z or NR a Rb where R a and Rb are

a) independently hydrogen,

15 a carbon based moiety of up to 30 carbon atoms optionally containing

heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and
carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms
selected from N, S and O and are optionally substituted by halogen, or

-OSi(Rf)3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon
20 atoms optionally containing heteroatoms selected from N, S and O and optionally substituted
by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which
optionally contain heteroatoms selected from N, S and O and are optionally substituted by
halogen; or

b) R a and R b together form a 5-7 member heterocyclic structure of 1-3
25 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of

1- 3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based
substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N,
S and O and are optionally substituted by halogen; or

c) one of R a or R b is -C(O)-, a C r C 5 divalent alkylene group or a substituted Ci-
30 C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5

101

members, wherein the substituents of the substituted C1-C5 divalent alkylene group are
selected from the group consisting of halogen, hydroxy, and carbon based substituents of up
to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are
optionally substituted by halogen;

5 where B is substituted, L is substituted or L 1 is additionally substituted, the

substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where
n is 0-3;

wherein each W is independently selected from the group consisting of -CN, -C0 2 R 7 ,
-C(0)NR 7 R 7 , -C(0)-R 7 , -N0 2 , -OR 7 , -SR 7 , -NR 7 R 7 , -NR 7 C(0)OR 7 , -NR 7 C(0)R 7 , -Q-Ar, and

10 carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected
from N, S and O and optionally substituted by one or more substituents independently
selected from the group consisting of -CN, -C0 2 R 7 , -C(0)R 7 , -C(0)NR 7 R 7 , -OR 7 , -SR 7 , -
NR 7 R 7 , -N0 2 , -NR 7 C(0)R 7 , -NR 7 C(0)OR 7 and halogen up to per-halo; with each R 7
independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally

15 containing heteroatoms selected from N, S and O and optionally substituted by halogen,

wherein Q is -O-, -S-, -N(R 7 )-, -(CH 2 ) m -, -C(O)-, -CH(OH)-, -(CH 2 ) m O-, -(CH 2 ) m S-,
-(CH 2 ) m N(R 7 )-, -0(CH 2 ) m - CHX\ -CX a 2 -, -S-(CH 2 ) m - and -N(R 7 )(CH 2 ) m -, where m- 1-3,
and X a is halogen;

Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the
20 group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen,
up to per-halo, and optionally substituted by Z„i, wherein nl is 0 to 3 and each Z is
independently selected from the group consisting of -CN, -C0 2 R 7 , -C(0)R 7 , -C(0)NR 7 R 7 , -
N0 2 , -OR 7 , - SR 7 -NR 7 R 7 , -NR 7 C(0)OR 7 , -NR 7 C(0)R 7 , and a carbon based moiety of up to
24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally
25 substituted by one or more substituents are selected from the group consisting of -CN, -
C0 2 R 7 , -COR 7 , -C(0)NR 7 R 7 , -OR 7 , -SR 7 , -N0 2 , -NR 7 R 7 , -NR 7 C(0)R 7 , and -NR 7 C(0)OR 7 ,
with R 7 as defined above; and

wherein M is one or more bridging groups selected from the group consisting of -0-, -S-, -
N(R 7 )-, -(CH 2 ) m -, -C(O)-, -CH(OH)-, -(CH 2 ) m O-, -(CH 2 ) m S-, -(CH 2 ) m N(R 7 )-, -0(CH 2 ) m -
30 CHX\ -CX a 2 -, -S-(CH 2 ) m - and -N(R 7 )(CH 2 ) m -, where m= 1-3, X a is halogen.

102

39. A compound of Formula I:

A - D - B (I)
5 or a pharmaceutical^ acceptable salt thereof, wherein
D is -NH-C(0)-NH-,

A is a substituted moiety of up to 40 carbon atoms of the formula: -L-CM-L 1 ) q ,
where L is a substituted or unsubstituted phenyl or peritoneal moiety bound directly to D, L 1
comprises a substituted phenyl, peritoneal or pyrimidinyl moiety, M is a bridging group
10 having at least one atom, q is an integer of from 1-3; and

B is a substituted or unsubstituted phenyl or pyridine group bound directly to D,

wherein L 1 is substituted by at least one substituent selected from the group consisting
of -S0 2 R x , -C(0)R x and -C(NR y ) R z ,

R y is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally
15 containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per
halo, and ;

R z is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally
containing heteroatoms selected from N, S and O and optionally substituted by halogen,
hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain
20 heteroatoms selected from N, S and O and are optionally substituted by halogen;

R x is R z or NR a R b where R a and R b are

a) independently hydrogen,

a carbon based moiety of up to 30 carbon atoms optionally containing
heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and
25 carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms
selected from N, S and O and are optionally substituted by halogen, or

-OSi(Rf)3 where R t - is hydrogen or a carbon based moiety of up to 24 carbon
atoms optionally containing heteroatoms selected from N, S and O and optionally substituted
by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which

103

optionally contain heteroatoms selected from N, S and O and are optionally substituted by
halogen; or

b) R a and R b together form a 5-7 member heterocyclic structure of 1-3
heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of

5 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based
substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N,
S and O and are optionally substituted by halogen; or

c) one of R a or R b is -C(O)-, a C1-C5 divalent alkylene group or a substituted Ci-
C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5

10 members, wherein the substituents of the substituted C1-C5 divalent alkylene group are
selected from the group consisting of halogen, hydroxy, and carbon based substituents of up
to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are
optionally substituted by halogen;

where B is substituted, L is substituted or L l is additionally substituted, the

15 substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where
n is 0-3;

wherein each W is independently selected from the group consisting of -CN, -CO2R 7 ,
-C(0)NR 7 R 7 , -C(0)-R 7 , -N0 2 , -OR 7 , -SR 7 , -NR 7 R 7 , -NR 7 C(0)OR 7 , -NR 7 C(0)R 7 , -Q-M and
carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected
20 from N, S and O and optionally substituted by one or more substituents independently
selected from the group consisting of -CN, -C0 2 R 7 , -C(0)R 7 , -C(0)NR 7 R 7 , -OR 7 , -SR 7 , -
NR 7 R 7 , -N0 2 , -NR 7 C(0)R 7 , -NR 7 C(0)OR 7 and halogen up to per-halo; with each R 7
independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally
containing heteroatoms selected from N, S and O and optionally substituted by halogen,

25 wherein Q is -O-, -S-, -N(R 7 )-, -(CH 2 ) m -, -C(O)-, -CH(OH)-, -(CH 2 ) m O-, -(CH 2 ) m S-,

-(CH 2 ) m N(R 7 )-, -0(CH 2 V CHX a -, -CX a 2 -, -S-(CH 2 )m- and -N(R 7 )(CH 2 ) m -, where m- 1-3,
and X a is halogen;

Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the
group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen;
30 up to per-halo, and optionally substituted by Z n i, wherein nl is 0 to 3 and each Z is

104

independently selected from the group consisting of -CN, -C0 2 R 7 , -C(0)R 7 , -C(0)NR 7 R 7 , -
N0 2 , -OR 7 , - SR 7 -NR 7 R 7 , -NR 7 C(0)OR 7 , -NR 7 C(0)R 7 , and a carbon based moiety of up to
24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally
substituted by one or more substituents selected from the group consisting of -CN, -C0 2 R , -
COR 7 , -C(0)NR 7 R 7 , -OR 7 , -SR 7 , -N0 2 , -NR 7 R 7 , -NR 7 C(0)R 7 , and -NR 7 C(0)OR 7 ; and
wherein M is one or more bridging groups selected from the group consisting of -O-, -S-, -
N(R 7 )-, -(CH 2 ) m -, -C(O)-, -CH(OH)-, -(CH 2 ) m O-, -(CH 2 ) m S-, -(CH 2 ) m N(R 7 )-, -0(CH 2 ) m -
CHX\ -CX a 2 -, -S-(CH 2 ) m - and -N(R 7 )(CH 2 ) m -, where m= 1-3, X a is halogen.

40. A compound as in claim 38 wherein the cyclic structures of B and L bound
directly to D are not substituted in the ortho position by-OH.

41. A compound as in claim 38 wherein the cyclic structures of B and L bound
directly to D are not substituted in the ortho position by a moiety having an ionizable
hydrogen and a pKa of 10 or less.

42. A compound as in claim 39 wherein the cyclic structures of B and L bound
directly to D are not substituted in the ortho position by-OH.

43. A compound as in claim 39 wherein the cyclic structures of B and L bound
directly to D are not substituted in the ortho position by a moiety having an ionizable
hydrogen and a pKa of 10 or less.

44. A compound as in claim 38 wherein substituents for B and L and additional
substituents for L 1 , are selected from the group consisting of Ct-Cio alkyl up to per halo
substituted C r Cio alkyl, CN, OH, halogen, C1-C10 alkoxy and up to per halo substituted C,-
C10 alkoxy.

45. A compound as in claim 39 wherein substituents for B and L and additional
substituents for L 1 , are selected from the group consisting of C r Ci 0 alkyl up to per halo
substituted C r Cio alkyl, CN, OH, halogen, C r Cio alkoxy and up to per halo substituted d-
Cio alkoxy.

46. A compound of claim 38 wherein L 1 is substituted by C(0)R x or S0 2 R x .

47. A compound of claim 39 wherein L l is substituted by C(0)R x or S0 2 R x .

48. A compound of claim 46 wherein R x is NR a Rb and R a and R b are
independently hydrogen and a carbon based moiety of up to 30 carbon atoms optionally

105

containing heteroatoms selected from N, S and O and optionally substituted by halogen,
hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain
heteroatoms selected from N, S and O and are optionally substituted by halogen..

49. A compound of claim 47 wherein R x is NR a R b and R a and R b are
independently hydrogen and a carbon based moiety of up to 30 carbon atoms optionally
containing heteroatoms selected from N, S and O and optionally substituted by halogen,
hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain
heteroatoms selected from N, S and O and are optionally substituted by halogen.

50. A compound of claim 1 which is a pharmaceutically acceptable salt of a
compound of formula I selected from the group consisting of

a) basic salts of organic acids and inorganic acids selected from the group
consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,
methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic
acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid,
trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid,
fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid;
and

b) acid salts of organic and inorganic bases containing cations selected from the
group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic
substituted ammonium cations and aromatic substituted ammonium cations.

51. A compound of claim 2 which is a pharmaceutically acceptable salt of a
compound of formula I selected from the group consisting of

a) basic salts of organic acids and inorganic acids selected from the group
consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,
methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic
acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid,
trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid,
fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid;

and

106

b) acid salts of organic and inorganic bases containing cations selected from the
group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic
substituted ammonium cations and aromatic substituted ammonium cations.

52. A compound of claim 33 which is a pharmaceutically acceptable salt of a
5 compound of formula I selected from the group consisting of

a) basic salts of organic acids and inorganic acids selected from the group
consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,
methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic
acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid,

10 trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid,
fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid;
and

b) acid salts of organic and inorganic bases containing cations selected from the
group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic

15 substituted ammonium cations and aromatic substituted ammonium cations.

53. A compound of claim 38 which is a pharmaceutically acceptable salt of a
compound of formula I selected from the group consisting of

a) basic salts of organic acids and inorganic acids selected from the group
consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,
20 methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic
acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid,
trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid,
fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid;
and

25 b) acid salts of organic and inorganic bases containing cations selected from the

group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic
substituted ammonium cations and aromatic substituted ammonium cations.
54. A compound of claim 39 which is a pharmaceutically acceptable salt of a compound
of formula I selected from the group consisting of

107

a) basic salts of organic acids and inorganic acids selected from the group
consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,
methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic
acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid,
trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid,
fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid;
and

b) acid salts of organic and inorganic bases containing cations selected from the
group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic
substituted ammonium cations and aromatic substituted ammonium cations.

55. A pharmaceutical composition comprising a compound of claim 1 or a
pharmaceutically acceptable salt of a compound of formula I , and a physiologically
acceptable carrier.

56. A pharmaceutical composition comprising a compound of claim 2 consistent
with fQrmula I or a pharmaceutically acceptable salt thereof, and a physiologically
acceptable carrier.

57. A pharmaceutical composition comprising a compound of claim 33 consistent
with formula I or a pharmaceutically acceptable salt thereof, and a physiologically
acceptable carrier.

58. A pharmaceutical composition comprising a compound of claim 38 consistent
with formula I or a pharmaceutically acceptable salt thereof, and a physiologically
acceptable carrier.

59. A pharmaceutical composition comprising a compound of claim 39 consistent
with formula I or a pharmaceutically acceptable salt thereof and a physiologically
acceptable carrier.

60. A compound selected from the group consisting of
3-tert butyl phenyl ureas of Table 1 above;

5-tert butyl-2-methoxyphenyl ureas of Table 2 above;

108

5-(trifluoromethyl)-2 phenyl ureas of Table 3 above;
3-(trifluoromethyl) -4 chlorophenyl ureas of Table 4 above;
3-(trifluoromethyl)-4-bromophenyl ureas of Table 5 above;
5-(trifluoromethyl)-4-chloro-2 methoxyphenyl ureas of Table 6 above; and
ureas 1 0 1 - 1 03 in Table 7 above.

61 . A compound selected from the group consisting of
the 3-tert butyl phenyl ureas:

A r -(3-rerr-butylphenyi)-iV'-(4-(3-(A r -methylcarbamoyl)phenoxy)phenyl urea and
A r -(3-^r?-butylphenyl)-iV-(4-(4-acetylphenoxy)phenyl urea;

the 5-rerr-butyl-2-methoxyphenyl ureas:

A^-(5-re^butyl-2-methoxyphenyl)-iV-(4-(l,3-dioxoisoindolin-5-yloxy)phenyl) urea,
A r -(5-rer?-butyl-2-methoxyphenyl)-iV , -(4-(i-oxoisoindolin-5-yloxy)phenyl) urea,
iV-(5-fer?-butyl-2-methoxyphenyl)-A r -(4-(4-methoxy-3-(A/ P -
methylcarbamoyl)phenoxy)phenyl) urea and

^(5_, e ^butyl-2-methoxyphe urea ^
the 2-methoxy-5-trifluoromethyl)phenyl ureas:

Ar-(2-methoxy-5Ktrifluoromethyl)phenyl)-A^-(3-(2-carbamoyl-4-pyridylo^ urea,

A^-methoxy-S-Ctrifluoromethy^^

pyridyloxy)phenyl) urea,

^-(2-methoxy-5-(trifluoromethyl)phen^ urea,

A42-methoxy-5-(trifluoromethyl)pte

pyridyloxy)phenyl) urea,

A r ^2-methoxy-5Ktrinuoromethyl)phenyl)-A r ^<4-(2KA r -methylcarbamoyl)-4-
pyridylthio)phenyl) urea,

N-(2-methoxy-5^trifluorom^

pyridyloxy))phenyl) urea and

109

AA(2-methoxy-5-(trifluoromethy^

pyridyioxy))phenyl) urea;

the 4-chloro-3-(trifluoromethyl)phenyl ureas:

iV-(4-chloro-3<trifluoromethy^ urea,

A^(4-chloro-3Ktrifluoromethy^^

urea,

^(4-chloro-3Ktrifluoro urea ^

^V-(4-chloro-3 -(trifluoromethyl)phenyl)-^ '-(4<2-(^-methylcarbamoyl)-4-pyridyloxy)phenyl)

urea.

the 4-romo-3-(trifluoromethyl)phenyl ureas:

7V-(4-bromo0^trifluoromethyl)pte

urea,

^4-bromo-3-(trifluoromethyl^
urea,

iV<4-bromo-3-(trifluoromethyl^^
urea,

AK4-bromo-3Ktrifluoromethyl^

pyridyloxy))phenyl) urea and
A^(4-bromo^-(trifluoromethyl)pte
pyridyloxy))phenyl) urea; and

the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas:
A42-methoxy-4-chloro-5-(trinuoro^
pyridyloxy)phenyl) urea,
A^(2-methoxy-4-chloro-5-(tri^
pyridyloxy)phenyl) urea,

A r -(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-A/ r '-(2-chloro-4-(2-(A r -
methylcarbamoyl)(4-pyridyloxy))phenyl) urea and

A r -(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-A r '-(3-chloro-4-(2-(A r -
methylcarbamoyl)(4-pyridyloxy))phenyl) urea.

110

62. A method for the treatment of a cancerous cell growth mediated by raf kinase,
comprising administering a compound of Formula I of claim 1 .

63 . A method for the treatment of a cancerous cell growth mediated by raf kinase,
5 comprising administering a compound of Formula I of claim 33 .

64. A method for the treatment of a cancerous cell growth mediated by raf kinase,
comprising administering a compound of Formula I of claim 38.

65. A method for the treatment of a cancerous cell growth mediated by raf kinase,
comprising administering a compound of Formula I of claim 39.

L0 66. A method for the treatment of a cancerous cell growth mediated by raf kinase,

comprising administrating a compound selected from the group consisting of

3-tert butyl phenyl ureas of Table 1 above;

5-tert butyl-2-methoxyphenyl ureas of Table 2 above;

5-(trifluoromethyl)-2 phenyl ureas of Table 3 above;
15 3-(trifluoromethyl) -4 chlorophenyl ureas of Table 4 above;

3-(trifluoromethyl)-4-bromophenyl ureas of Table 5 above;

5-(trifluoromethyl)-4-chloro-2 methoxyphenyl ureas of Table 6 above; and

ureas 1 0 1 - 1 03 in Table 7 above.

67. A method for the treatment of a cancerous cell growth mediated by raf kinase,
20 comprising administrating a compound selected from the group consisting of

the 3-tert butyl phenyl ureas:

A^K3-^^butylphenyl)-iV , K4-(3-(^-rnethylcarbamoyl)phenoxy)phenyl urea and
A^-(3-^r/-butylphenyl)-A r '-(4-(4-acetylphenoxy)phenyl urea;

25 the 5 -tert-buty 1-2 -methoxyphenyl ureas:

^(5-^^-butyl-2-methoxyphenyl)-iV'-(4-(l,3-dioxoisoindolin-5-yloxy)phenyl) urea,
7V-(5-^-butyl-2-methoxyphenyl)-A^H4Kl-oxoisoindolin-5-yloxy)pheny0 urea,

111

T

T

.V-(5-re^butyl-2-methoxyphenyl)-A^'K4^4-methoxy-3-(iV-
methylcarbamoyl)phenoxy)phenyl) urea and

AT-(5-terNbutyl-2-methoxypheny^ urea;

5 the 2-methoxy-5-trifluoromethyl)phenyl ureas:

^2-methoxy-5^trifluorom urea,

A42-methoxy-5-(trifluoromethyl)phen^

pyridyloxy)phenyl) urea,

tf-(2-methoxy-5<trifluorom^ urea >
10 A42-methoxy-5-(trinuoromethyl)phenyl>^
pyridyloxy)phenyl) urea,
//-(2-methoxy-5-(trifluoro^
pyridylthio)phenyl) urea,

15 A^(2-methoxy-5-(trifluoromethyl^

pyridyloxy))phenyl) urea and

AH2-methoxy-5-(trinuoromethyl)phenyO

pyridyloxy))phenyl) urea;

20 the 4-chloro-3-(trifluoromethyl)phenyl ureas:

^-(4-chloroO-(trifluoromethyl)phenyl)-A^'^3<2-carbamoyl-4-pyridyloxy)phenyl) urea,

^-(4-chloroO-(trifluoromethyl)pte^^

urea,

^-(4-chloro-3-(trifluoromethy^ urea and

25 A44-chloro-3^trifluoromethyl)phenyl)wV^^^
urea;

the 4-romo-3-(trifluoromethyl)phenyl ureas:
iV-(4-bromoO-(trifluoromethyl)phenyl^

30 urea,

^4-bromoO-(trifluoromethyl)pte
urea,

112

v V-(4-bromo-3-(trifluoromethyl)phen^
urea,

^-(4-bromoO-(trifluorome^
pyridyloxy))phenyl) urea and
Ar-(4-bromo-3-(trifluqrometh^
pyridyloxy))phenyl) urea; and

the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas:
A^2-methoxy-4-chloro-5-(triflu^
pyridyloxy)phenyl) urea,
A42-methoxy-4-chloro-5-(tri^
pyridyloxy)phenyl) urea,

A r -(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-A r -(2-chloro-4-(2-(7V-
methylcarbamoyl)(4-pyridyloxy))phenyl) urea and
A42-methoxy-4-chloro-5-(trifluorome^
methylcarbamoyl)(4-pyridyloxy))phenyl) urea.

113

Abstract of the Disclosure

This invention relates to the use of a group of aryl ureas in treating raf mediated
diseases, and pharmaceutical compositions for use in such therapy.

114